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Current papers in developmental biology and gene function

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Tuesday, December 31st, 2013

Poulton, J. S., Mu, F. W., Roberts, D. M. and Peifer, M. (2013). APC2 and Axin promote mitotic fidelity by facilitating centrosome separation and cytoskeletal regulation. Development 140: 4226-4236. PubMed ID: 24026117
Summary: To ensure the accurate transmission of genetic material, chromosome segregation must occur with extremely high fidelity. Segregation errors lead to chromosomal instability (CIN), with deleterious consequences. Mutations in the tumor suppressor Adenomatous polyposis coli (APC) initiate most colon cancers and have also been suggested to promote disease progression through increased CIN, but the mechanistic role of APC in preventing CIN remains controversial. Using fly embryos as a model, this study investigated the role of APC proteins in CIN. The findings suggest that APC2 loss leads to increased rates of chromosome segregation error. This occurs through a cascade of events beginning with incomplete centrosome separation leading to failure to inhibit formation of ectopic cleavage furrows, which result in mitotic defects and DNA damage. Several hypotheses related to the mechanism of action of APC2 were tested, revealing that APC2 functions at the embryonic cortex with several protein partners, including Axin, to promote mitotic fidelity. These in vivo data demonstrate that APC2 protects genome stability by modulating mitotic fidelity through regulation of the cytoskeleton.

Lu, M. S. and Prehoda, K. E. (2013). A NudE/14-3-3 pathway coordinates dynein and the kinesin Khc73 to position the mitotic spindle. Dev Cell 26: 369-380. PubMed ID: 23987511
Summary: Mitotic spindle position is controlled by interactions of cortical molecular motors with astral microtubules. In animal cells, Partner of Inscuteable (Pins) acts at the cortex to coordinate the activity of Dynein and Kinesin-73 (Khc73; KIF13B in mammals) to orient the spindle. Though the two motors move in opposite directions, their synergistic activity is required for robust Pins-mediated spindle orientation. This study identified a physical connection between Dynein and Khc73 that mediates cooperative spindle positioning. Khc73's motor and MBS domains link Pins to microtubule plus ends, while its stalk domain is necessary for Dynein activation and precise positioning of the spindle. A motif in the stalk domain binds, in a phospho-dependent manner, 14-3-3zeta, which dimerizes with 14-3-3epsilon. The 14-3-3zeta/epsilon heterodimer binds the Dynein adaptor NudE to complete the Dynein connection. The Khc73 stalk/14-3-3/NudE pathway defines a physical connection that coordinates the activities of multiple motor proteins to precisely position the spindle.

Shields, A. R., Spence, A. C., Yamashita, Y. M., Davies, E. L. and Fuller, M. T. (2014). The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells. Development 141: 73-82. PubMed ID: 24346697
Summary: Specialized microenvironments, or niches, provide signaling cues that regulate stem cell behavior. In the Drosophila testis, the JAK-STAT signaling pathway regulates germline stem cell (GSC) attachment to the apical hub and somatic cyst stem cell (CySC) identity. This study demonstrates that chickadee, the Drosophila gene that encodes profilin, is required cell autonomously to maintain GSCs, possibly facilitating localization or maintenance of E-cadherin to the GSC-hub cell interface. Germline specific overexpression of Adenomatous Polyposis Coli 2 (APC2) rescued GSC loss in chic hypomorphs, suggesting an additive role of APC2 and F-actin in maintaining the adherens junctions that anchor GSCs to the niche. In addition, loss of chic function in the soma resulted in failure of somatic cyst cells to maintain germ cell enclosure and overproliferation of transit-amplifying spermatogonia.

December 30th, 2013

Olesnicky, E. C., Killian, D. J., Garcia, E., Morton, M. C., Rathjen, A. R., Sola, I. E. and Gavis, E. R. (2013). . Extensive Use of RNA Binding Proteins in Drosophila Sensory Neuron Dendrite Morphogenesis. G3 (Bethesda). PubMed ID: 24347626
Summary: The large number of RNA binding proteins and translation factors encoded in the Drosophila and other metazoan genomes predicts widespread use of post-transcriptional regulation in cellular and developmental processes. Previous studies identified roles for several RNA binding proteins in dendrite branching morphogenesis of Drosophila larval sensory neurons. To determine the large contribution of post-transcriptional gene regulation to neuronal morphogenesis, an RNAi screen was constructed to identify Drosophila proteins annotated as either RNA binding proteins or translation factors that function in producing the complex dendritic trees of larval class IV dendritic arborization neurons. Eighty-eight such proteins were identified whose knock-down resulted in aberrant dendritic morphology including alterations in dendritic branch number, branch length, field size, and patterning of the dendritic tree. In particular, splicing and translational initiation factors were associated with distinct and characteristic phenotypes, suggesting that different morphogenetic events are best controlled at specific steps in post-transcriptional mRNA metabolism. Many of the factors identified in the screen have been implicated in controlling the subcellular distributions and translation of maternal mRNAs; thus, common post-transcriptional regulatory strategies may be employed in neurogenesis and in the generation of asymmetry in the female germline and embryo.

Heraud-Farlow, J. E. et al. (2013). Staufen2 Regulates Neuronal Target RNAs. Cell Reports 5: 1511-1518
Summary: RNA-binding proteins play crucial roles in directing RNA translation to neuronal synapses. Staufen2 (Stau2; see Drosophila Staufen) has been implicated in both dendritic RNA localization and synaptic plasticity in mammalian neurons. This study reports the identification of functionally relevant Stau2 target mRNAs in neurons. The majority of Stau2-copurifying mRNAs expressed in the hippocampus are present in neuronal processes, further implicating Stau2 in dendritic mRNA regulation. Stau2 targets are enriched for secondary structures similar to those identified in the 3′ UTRs of Drosophila Staufen targets. Next, Stau2 was shown to regulate steady-state levels of many neuronal RNAs, and its targets are predominantly downregulated in Stau2-deficient neurons. Detailed analysis confirms that Stau2 stabilizes the expression of one synaptic signaling component, the regulator of G protein signaling 4 (Rgs4) mRNA, via its 3′ UTR. This study defines the global impact of Stau2 on mRNAs in neurons, revealing a role in stabilization of the levels of synaptic targets.

Gromak, N., et al. (2013). Drosha is the main RNase III-like enzyme involved in the process of microRNA (miRNA) biogenesis in the nucleus. Cell Reports, Volume 5, Issue 6, 1499-1510>
Summary: Using whole-genome ChIP-on-chip analysis, this study demonstrates that, in addition to miRNA sequences, Drosha (see Drosophila Drosha) specifically binds promoter-proximal regions of many human genes in a transcription-dependent manner. This binding is not associated with miRNA production or RNA cleavage. Drosha knockdown in HeLa cells downregulates nascent gene transcription, resulting in a reduction of polyadenylated mRNA produced from these gene regions. Furthermore, it was shown that this function of Drosha is dependent on its N-terminal protein-interaction domain, which associates with the RNA-binding protein CBP80 (see Drosophila CBP80) and RNA Polymerase II (see Drosophila Pol2). Consequently, this study has uncovered a previously unsuspected RNA cleavage-independent function of Drosha in the regulation of human gene expression.

Sunday, December 29th

Sudhakaran, I. P., Hillebrand, J., Dervan, A., Das, S., Holohan, E. E., Hulsmeier, J., Sarov, M., Parker, R., Vijayraghavan, K. and Ramaswami, M. (2013). FMRP and Ataxin-2 function together in long-term olfactory habituation and neuronal translational control. Proc Natl Acad Sci U S A. PubMed ID: 24344294
Summary: Fragile X mental retardation protein (FMRP) and Ataxin-2 (Atx2) are triplet expansion disease- and stress granule-associated proteins implicated in neuronal translational control and microRNA function. This study shows that Drosophila FMRP (dFMR1) is required for long-term olfactory habituation (LTH), a phenomenon dependent on Atx2-dependent potentiation of inhibitory transmission from local interneurons (LNs) to projection neurons (PNs) in the antennal lobe. dFMR1 is also required for LTH-associated depression of odor-evoked calcium transients in PNs. Strong transdominant genetic interactions among dFMR1, atx2, the deadbox helicase me31B, and argonaute1 (ago1) mutants, as well as coimmunoprecitation of dFMR1 with Atx2, indicate that dFMR1 and Atx2 function together in a microRNA-dependent process necessary for LTH. Consistently, PN or LN knockdown of dFMR1, Atx2, Me31B, or the miRNA-pathway protein GW182 increases expression of a Ca2+/calmodulin-dependent protein kinase II (CaMKII) translational reporter. Moreover, brain immunoprecipitates of dFMR1 and Atx2 proteins include CaMKII mRNA, indicating respective physical interactions with this mRNA. Because CaMKII is necessary for LTH, these data indicate that fragile X mental retardation protein and Atx2 act via at least one common target RNA for memory-associated long-term synaptic plasticity. The observed requirement in LNs and PNs supports an emerging view that both presynaptic and postsynaptic translation are necessary for long-term synaptic plasticity. However, whereas Atx2 is necessary for the integrity of dendritic and somatic Me31B-containing particles, dFmr1 is not. Together, these data indicate that dFmr1 and Atx2 function in long-term but not short-term memory, regulating translation of at least some common presynaptic and postsynaptic target mRNAs in the same cells.

Corbett-Detig, R. B., Zhou, J., Clark, A. G., Hartl, D. L. and Ayroles, J. F. (2013). Genetic incompatibilities are widespread within species. Nature 504: 135-137. PubMed ID: 24196712
Summary: The importance of epistasis--non-additive interactions between alleles--in shaping population fitness has long been a controversial topic, hampered in part by lack of empirical evidence. Traditionally, epistasis is inferred on the basis of non-independence of genotypic values between loci for a given trait. However, epistasis for fitness should also have a genomic footprint. To capture this signal, a simple approach was developed that relies on detecting genotype ratio distortion as a sign of epistasis, and this method was applied to a large panel of Drosophila melanogaster recombinant inbred lines. That instances of genotype ratio distortion represent loci with epistatic fitness effects was confirm experimentally; it was conservatively estimated that any two haploid genomes in this study are expected to harbour 1.15 pairs of epistatically interacting alleles. This observation has important implications for speciation genetics, as it indicates that the raw material to drive reproductive isolation is segregating contemporaneously within species and does not necessarily require, as proposed by the Dobzhansky-Muller model, the emergence of incompatible mutations independently derived and fixed in allopatry. The relevance of these results extends beyond speciation, as it demonstrates that epistasis is widespread but that it may often go undetected owing to lack of statistical power or lack of genome-wide scope of the experiments.

Kohn, N. R., Reaume, C. J., Moreno, C., Burns, J. G., Sokolowski, M. B. and Mery, F. (2013). Social environment influences performance in a cognitive task in natural variants of the foraging gene. PLoS One 8: e81272. PubMed ID: 24349049
Summary: In Drosophila melanogaster, natural genetic variation in the foraging gene affects the foraging behaviour of larval and adult flies, larval reward learning, adult visual learning, and adult aversive training tasks. Sitters (fors) are more sedentary and aggregate within food patches whereas rovers (forR) have greater movement within and between food patches, suggesting that these natural variants are likely to experience different social environments. It is hypothesized that social context would differentially influence rover and sitter behaviour in a cognitive task. Adult rover and sitter performance was measured in a classical olfactory training test in groups and alone. All flies were reared in groups, but fly training and testing were done alone and in groups. Sitters trained and tested in a group had significantly higher learning performances compared to sitters trained and tested alone. Rovers performed similarly when trained and tested alone and in a group. In other words, rovers learning ability is independent of group training and testing. This suggests that sitters may be more sensitive to the social context than rovers. These differences in learning performance can be altered by pharmacological manipulations of PKG activity levels, the foraging (for) gene's gene product. Learning and memory is also affected by the type of social interaction (being in a group of the same strain or in a group of a different strain) in rovers, but not in sitters. These results suggest that for mediates social learning and memory in D. melanogaster.

Saturday, December 28th

Zhang, Y., et al. (2013). Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature 504: 306-310. PubMed ID: 24213634
Summary: In multicellular organisms, transcription regulation is one of the central mechanisms modelling lineage differentiation and cell-fate determination. Transcription requires dynamic chromatin configurations between promoters and their corresponding distal regulatory elements. It is believed that their communication occurs within large discrete foci of aggregated RNA polymerases termed transcription factories in three-dimensional nuclear space. However, the dynamic nature of chromatin connectivity has not been characterized at the genome-wide level. In this study, through a chromatin interaction analysis with paired-end tagging approach using an antibody that primarily recognizes the pre-initiation complexes of RNA polymerase II, the transcriptional interactomes of three mouse cells of progressive lineage commitment were explored, including pluripotent embryonic stem cells, neural stem cells and neurosphere stem/progenitor cells. Global chromatin connectivity maps reveal approximately 40,000 long-range interactions, suggest precise enhancer-promoter associations and delineate cell-type-specific chromatin structures. Analysis of the complex regulatory repertoire shows that there are extensive colocalizations among promoters and distal-acting enhancers. Most of the enhancers associate with promoters located beyond their nearest active genes, indicating that the linear juxtaposition is not the only guiding principle driving enhancer target selection. Although promoter-enhancer interactions exhibit high cell-type specificity, promoters involved in interactions are found to be generally common and mostly active among different cells. Chromatin connectivity networks reveal that the pivotal genes of reprogramming functions are transcribed within physical proximity to each other in embryonic stem cells, linking chromatin architecture to coordinated gene expression. This study sets the stage for the full-scale dissection of spatial and temporal genome structures and their roles in orchestrating development.

Kieffer-Kwon, K. R., et al. (2013). Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell 155: 1507-1520. PubMed ID: 24360274
Summary: A key finding of the ENCODE project is that the enhancer landscape of mammalian cells undergoes marked alterations during ontogeny. However, the nature and extent of these changes are unclear. As part of the NIH Mouse Regulome Project, DNaseI hypersensitivity, ChIP-seq, and ChIA-PET technologies were combined to map the promoter-enhancer interactomes of pluripotent ES cells and differentiated B lymphocytes. It was confirmd that enhancer usage varies widely across tissues. Unexpectedly, this feature was found to extend to broadly transcribed genes, including Myc and Pim1 cell-cycle regulators, which associate with an entirely different set of enhancers in ES and B cells. By means of high-resolution CpG methylomes, genome editing, and digital footprinting, it was shown that these enhancers recruit lineage-determining factors. Furthermore, it was demonstrated that the turning on and off of enhancers during development correlates with promoter activity. It is proposed that organisms rely on a dynamic enhancer landscape to control basic cellular functions in a tissue-specific manner.

Nord, A. S. et al. (2013). Rapid and Pervasive Changes in Genome-wide Enhancer Usage during Mammalian Development. Cell 155: 1521-1531. PubMed ID: 24360275
Summary: Enhancers are distal regulatory elements that can activate tissue-specific gene expression and are abundant throughout mammalian genomes. Although substantial progress has been made toward genome-wide annotation of mammalian enhancers, their temporal activity patterns and global contributions in the context of developmental in vivo processes remain poorly explored. This study used epigenomic profiling forH3K27ac (see Drosophila H3), a mark of active enhancers, coupled to transgenic mouse assays to examine the genome-wide utilization of enhancers in three different mouse tissues across seven developmental stages. The majority of the ∼90,000 enhancers identified exhibited tightly temporally restricted predicted activity windows and were associated with stage-specific biological functions and regulatory pathways in individual tissues. Comparative genomic analysis revealed that evolutionary conservation of enhancers decreases following midgestation across all tissues examined. The dynamic enhancer activities uncovered in this study illuminate rapid and pervasive temporal in vivo changes in enhancer usage that underlie processes central to development and disease.

Friday, December 27th

Sulkowski, M., Kim, Y. J. and Serpe, M. (2013). Postsynaptic glutamate receptors regulate local BMP signaling at the Drosophila neuromuscular junction. Development. PubMed ID: 24353060
Summary: Effective communication between pre- and postsynaptic compartments is required for proper synapse development and function. At the Drosophila neuromuscular junction (NMJ), a retrograde BMP signal functions to promote synapse growth, stability and homeostasis and coordinates the growth of synaptic structures. Retrograde BMP signaling triggers accumulation of the pathway effector pMad in motoneuron nuclei and at synaptic termini. Nuclear pMad, in conjunction with transcription factors, modulates the expression of target genes and instructs synaptic growth; a role for synaptic pMad remains to be determined. This study reports that pMad signals are selectively lost at NMJ synapses with reduced postsynaptic sensitivities. Despite this loss of synaptic pMad, nuclear pMad persisted in motoneuron nuclei, and expression of BMP target genes was unaffected, indicating a specific impairment in pMad production/maintenance at synaptic termini. During development, synaptic pMad accumulation followed the arrival and clustering of ionotropic glutamate receptors (iGluRs) at NMJ synapses. Synaptic pMad was lost at NMJ synapses developing at suboptimal levels of iGluRs and Neto, an auxiliary subunit required for functional iGluRs. Genetic manipulations of non-essential iGluR subunits revealed that synaptic pMad signals specifically correlated with the postsynaptic type-A glutamate receptors. Altering type-A receptor activities via protein kinase A (PKA) revealed that synaptic pMad depends on the activity and not the net levels of postsynaptic type-A receptors. Thus, synaptic pMad functions as a local sensor for NMJ synapse activity and has the potential to coordinate synaptic activity with a BMP retrograde signal required for synapse growth and homeostasis.

Hong, S. T. and Choi, K. W. (2013). TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster. Nat Commun 4: 2986. PubMed ID: 24352200
Summary: Translationally controlled tumour protein (TCTP) is implicated in growth regulation and cancer. Recently, human TCTP has been suggested to play a role in the DNA damage response by forming a complex with ataxia telangiectasia-mutated (ATM) kinase. However, the exact nature of this interaction and its roles in vivo remained unclear. This study utilized Drosophila as an animal model to study the nuclear function of Drosophila TCTP (dTCTP). dTCTP mutants show increased radiation sensitivity during development as well as strong genetic interaction with dATM mutations, resulting in severe defects in developmental timing, organ size and chromosome stability. Drosophila ATM (dATM) was identified as a direct binding partner of dTCTP, and a mechanistic basis is described for dATM activation by dTCTP. Altogether, this study provides the first in vivo evidence for direct modulation of dATM activity by dTCTP in the control of genome stability and organ development.

Thursday, December 26th

Subramanian, M., Jayakumar, S., Richhariya, S. and Hasan, G. (2013). Loss of IP3 receptor function in neuropeptide secreting neurons leads to obesity in adult Drosophila. BMC Neurosci 14: 157. PubMed ID: 24350669
Summary: Intracellular calcium signaling regulates a variety of cellular and physiological processes. The inositol 1,4,5 trisphosphate receptor (IP3R) is a ligand gated calcium channel present on the membranes of endoplasmic reticular stores. Previous work has shown that Drosophila mutants for the IP3R (itprku) become unnaturally obese as adults with excessive storage of lipids on a normal diet. While the phenotype manifests in cells of the fat body, genetic studies suggest dysregulation of a neurohormonal axis. This study shows that knockdown of the IP3R, either in all neurons or in peptidergic neurons alone, mimics known itpr mutant phenotypes. The peptidergic neuron domain includes, but is not restricted to, the medial neurosecretory cells as well as the stomatogastric nervous system. Conversely, expression of an itpr+ cDNA in the same set of peptidergic neurons rescues metabolic defects of itprku mutants. Transcript levels of a gene encoding a gastric lipase CG5932 (magro), which is known to regulate triacylglyceride storage, can be regulated by itpr knockdown and over-expression in peptidergic neurons. Thus, the focus of observed itpr mutant phenotypes of starvation resistance, increased body weight, elevated lipid storage and hyperphagia derive primarily from peptidergic neurons. The present study shows that itpr function in peptidergic neurons is not only necessary but also sufficient for maintaining normal lipid metabolism in Drosophila. These results suggest that intracellular calcium signaling in peptidergic neurons affects lipid metabolism by both cell autonomous and non-autonomous mechanisms.

Rana, R., Carroll, C. E., Lee, H. J., Bao, J., Marada, S., Grace, C. R., Guibao, C. D., Ogden, S. K. and Zheng, J. J. (2013). Structural insights into the role of the Smoothened cysteine-rich domain in Hedgehog signalling. Nat Commun 4: 2965. PubMed ID: 24351982
Summary: Smoothened (Smo) is a member of the Frizzled (FzD) class of G-protein-coupled receptors (GPCRs), and functions as the key transducer in the Hedgehog (Hh) signalling pathway. Smo has an extracellular cysteine-rich domain (CRD), indispensable for its function and downstream Hh signalling. Despite its essential role, the functional contribution of the CRD to Smo signalling has not been clearly elucidated. However, given that the FzD CRD binds to the endogenous Wnt ligand, it has been proposed that the Smo CRD may bind its own endogenous ligand. This study presents the NMR solution structure of the Drosophila Smo CRD and describes interactions between the glucocorticoid budesonide (Bud) and the Smo CRDs from both Drosophila and human. These results highlight a function of the Smo CRD, demonstrating its role in binding to small-molecule modulators.

Wednesday, December 25th

Fitzsimons, H. L., Schwartz, S., Given, F. M. and Scott, M. J. (2013). The Histone Deacetylase HDAC4 Regulates Long-Term Memory in Drosophila. PLoS One 8: e83903. PubMed ID: 24349558
Summary: A growing body of research indicates that pharmacological inhibition of histone deacetylases (HDACs) correlates with enhancement of long-term memory and current research is concentrated on determining the roles that individual HDACs play in cognitive function. This study investigated the role of HDAC4 in long-term memory formation in Drosophila. Overexpression of HDAC4 in the adult mushroom body, an important structure for memory formation, was shown to result in a specific impairment in long-term courtship memory, but had no affect on short-term memory. Overexpression of an HDAC4 catalytic mutant also abolished LTM, suggesting a mode of action independent of catalytic activity. It was also found that overexpression of HDAC4 results in a redistribution of the transcription factor MEF2 from a relatively uniform distribution through the nucleus into punctate nuclear bodies, where it colocalized with HDAC4. As MEF2 has also been implicated in regulation of long-term memory, these data suggest that the repressive effects of HDAC4 on long-term memory may be through interaction with MEF2. In the same genetic background, it was also found that RNAi-mediated knockdown of HDAC4 impairs long-term memory; therefore this study demonstrates that HDAC4 is not only a repressor of long-term memory, but also modulates normal memory formation.

Stefanatos, R. K., Bauer, C. and Vidal, M. (2013). p120 Catenin Is Required for the Stress Response in Drosophila. PLoS One 8: e83942. PubMed ID: 24349561
Summary: p120ctn is a ubiquitously expressed core component of cadherin junctions and essential for vertebrate development. Surprisingly, Drosophila p120ctn (dp120ctn) is dispensable for adherens junctions and development, which has discouraged Drosophila researchers from further pursuing the biological role of dp120ctn. This study demonstrate that dp120ctn loss results in increased heat shock sensitivity and reduced animal lifespan, which are completely rescued by ectopic expression of a dp120ctn-GFP transgene. Transcriptomic analysis revealed multiple relish/NF-kappaB target genes differentially expressed upon loss of dp120ctn. Importantly, this aberrant gene expression was rescued by overexpression of dp120ctn-GFP or heterozygosity for relish. These results uncover a novel role for dp120ctn in the regulation of animal stress response and immune signalling. This may represent an ancient role of p120ctn and can influence further studies in Drosophila and mammals.

Tuesday, December 24th

Kumsta, C., Ching, T. T., Nishimura, M., Davis, A. E., Gelino, S., Catan, H. H., Yu, X., Chu, C. C., Ong, B., Panowski, S. H., Baird, N., Bodmer, R., Hsu, A. L. and Hansen, M. (2013). Integrin-linked kinase modulates longevity and thermotolerance in C. elegans through neuronal control of HSF-1. Aging Cell. PubMed ID: 24314125
Summary: Integrin-signaling complexes play important roles in cytoskeletal organization and cell adhesion in many species. Components of the integrin-signaling complex have been linked to aging in both Caenorhabditis elegans and Drosophila, but the mechanisms underlying this function are unknown. This study investigated the role of Integrin-linked kinase (ILK), a key component of the integrin-signaling complex, in lifespan determination. Genetic reduction of ILK in both C. elegans and Drosophila increases resistance to heat stress, and leads to lifespan extension in C. elegans without majorly affecting cytoskeletal integrity. In C. elegans, longevity and thermotolerance induced by ILK depletion is mediated by the heat-shock factor-1 (HSF-1; see Drosophila HSF), a major transcriptional regulator of the heat-shock response (HSR). Reduction of ILK levels increases hsf-1 transcription and activation, and leads to enhanced expression of a subset of genes with roles in the HSR. Moreover, induction of HSR-related genes, longevity, and thermotolerance caused by ILK reduction required the thermosensory neuron AFD and interneuron AIY, which are known to play a critical role in the canonical HSR. Notably, ILK was expressed in neighboring neurons, but not in AFD or AIY, implying that ILK reduction initiates cell non-autonomous signaling through thermosensory neurons to elicit a non-canonical HSR. These results thus identify HSF-1 as a novel effector of the organismal response to reduced ILK levels, and show that ILK inhibition regulates HSF-1 in a cell non-autonomous fashion to enhance stress resistance and lifespan in C. elegans.

Housden, B. E., Terriente-Felix, A. and Bray, S. J. (2013). Context-dependent enhancer selection confers alternate modes of Notch regulation on argos. Mol Cell Biol. PubMed ID: 24324007
Summary: Wiring between signaling pathways differs according to context, as exemplified by interactions between Notch and EGFR pathways, which are cooperative in some contexts but antagonistic in others. To investigate mechanisms that underlie different modes of cross-talk, this study focused on argos, an EGFR pathway regulator in Drosophila which is up-regulated by Notch in adult muscle progenitors but is repressed in the wing. Results show that the alternate modes of cross-talk depend on the engagement of enhancers with opposite regulatory logic, which are selected by context-determining factors. This is likely to be a general mechanism for enabling the wiring between these pathways to switch according to context.

Monday, December 23rd

Aleksic, J., Ferrero, E., Fischer, B., Shen, S. P. and Russell, S. (2013) The role of Dichaete in transcriptional regulation during Drosophila embryonic development. BMC Genomics 14: 861. PubMed ID: 24314314
Summary: Group B Sox domain transcription factors play conserved roles in the specification and development of the nervous system in higher metazoans. In Drosophila, only two group B Sox genes, Dichaete and SoxN, have been shown to function during embryonic CNS development, providing a simple system for understanding the functions of this important class of regulators. Using a combination of transcriptional profiling and genome-wide binding analysis, over 1000 high confidence direct Dichaete target genes were identified in the Drosophila genome. Dichaete was shown to play key roles in CNS development, regulating aspects of the temporal transcription factor sequence that confer neuroblast identity. Dichaete also shows a complex interaction with Prospero in the pathway controlling the switch from stem cell self-renewal to neural differentiation. Dichaete potentially regulates many more genes in the Drosophila genome and was found to be associated with over 2000 mapped regulatory elements. This analysis suggests that Dichaete acts as a transcriptional hub, controlling multiple regulatory pathways during CNS development. These include a set of core CNS expressed genes that are also bound by the related Sox2 gene during mammalian CNS development. Furthermore, Dichaete was identified as one of the transcription factors involved in the neural stem cell transcriptional network, with evidence supporting the view that Dichaete is involved in controlling the temporal series of divisions regulating neuroblast identity.

Teves, S. S. and Henikoff, S. (2013). Transcription-generated torsional stress destabilizes nucleosomes. Nat Struct Mol Biol. PubMed ID: 24317489
Summary: As RNA polymerase II (Pol II) transcribes a gene, it encounters an array of well-ordered nucleosomes. How it traverses through this array in vivo remains unresolved. One model proposes that torsional stress generated during transcription destabilizes nucleosomes ahead of Pol II. This study describes a method for high-resolution mapping of underwound DNA, using next-generation sequencing, and shows that torsion is correlated with gene expression in Drosophila melanogaster cells. Accumulation of torsional stress, through topoisomerase inhibition, results in increased Pol II at transcription start sites. Whereas topoisomerase I inhibition results in increased nascent RNA transcripts, topoisomerase II inhibition causes little change. Despite the different effects on Pol II elongation, topoisomerase inhibition results in increased nucleosome turnover and salt solubility within gene bodies, thus suggesting that the elongation-independent effects of torsional stress on nucleosome dynamics contributes to the destabilization of nucleosomes.

Sunday, December 22nd

Bacaj, T., Wu, D., Yang, X., Morishita, W., Zhou, P., Xu, W., Malenka, R. C. and Sudhof, T. C. (2013). Synaptotagmin-1 and synaptotagmin-7 trigger synchronous and asynchronous phases of neurotransmitter release. Neuron 80: 947-959. PubMed ID: 24267651
Summary: In forebrain neurons, knockout of synaptotagmin-1 (Drosophila homolog: Synaptotagmin blocks fast Ca2+-triggered synchronous neurotransmitter release but enables manifestation of slow Ca2+-triggered asynchronous release. This study shows, using single-cell PCR, that individual hippocampal neurons abundantly coexpress two Ca2+-binding synaptotagmin isoforms, synaptotagmin-1 and synaptotagmin-7. In synaptotagmin-1-deficient synapses of excitatory and inhibitory neurons, loss of function of synaptotagmin-7 suppressed asynchronous release. This phenotype was rescued by wild-type but not mutant synaptotagmin-7 lacking functional Ca2+-binding sites. Even in synaptotagmin-1-containing neurons, synaptotagmin-7 ablation partly impaired asynchronous release induced by extended high-frequency stimulus trains. Synaptotagmins bind Ca2+ via two C2 domains, the C2A and C2B domains. Surprisingly, synaptotagmin-7 function selectively required its C2A domain Ca2+-binding sites, whereas synaptotagmin-1 function required its C2B domain Ca2+-binding sites. These data show that nearly all Ca2+-triggered release at a synapse is due to synaptotagmins, with synaptotagmin-7 mediating a slower form of Ca2+-triggered release that is normally occluded by faster synaptotagmin-1-induced release but becomes manifest upon synaptotagmin-1 deletion.

Hunter, G. L., Crawford, J. M., Genkins, J. Z. and Kiehart, D. P. (2013). Ion channels contribute to the regulation of cell sheet forces during Drosophila dorsal closure. . Development. [Epub ahead of print] PubMed ID: 24306105
Summary: Ion channels contribute to the regulation of dorsal closure in Drosophila, a model system for cell sheet morphogenesis. Ca2+ was found to be sufficient to cause cell contraction in dorsal closure tissues, as UV-mediated release of caged Ca2+ leads to cell contraction. Furthermore, endogenous Ca2+ fluxes correlate with cell contraction in the amnioserosa during closure, whereas the chelation of Ca2+ slows closure. Microinjection of high concentrations of the peptide GsMTx4, which is a specific modulator of mechanically gated ion channel function, causes increases in cytoplasmic free Ca2+ and actomyosin contractility and, in the long term, blocks closure in a dose-dependent manner. Two channel subunits, ripped pocket and dtrpA1 (TrpA1), were identified that play a role in closure and other morphogenetic events. Blocking channels leads to defects in force generation via failure of actomyosin structures, and impairs the ability of tissues to regulate forces in response to laser microsurgery. These results point to a key role for ion channels in closure, and suggest a mechanism for the coordination of force-producing cell behaviors across the embryo.

Saturday, December 21st

Law, A. L., Vehlow, A., Kotini, M., Dodgson, L., Soong, D., Theveneau, E., Bodo, C., Taylor, E., Navarro, C., Perera, U., Michael, M., Dunn, G. A., Bennett, D., Mayor, R. and Krause, M. (2013). Lamellipodin and the Scar/WAVE complex cooperate to promote cell migration in vivo. J Cell Biol. PubMed ID: 24247431
Summary: Cell migration is essential for development, but its deregulation causes metastasis. The Scar/WAVE complex is absolutely required for lamellipodia and is a key effector in cell migration, but its regulation in vivo is enigmatic. Lamellipodin (Lpd) controls lamellipodium formation through an unknown mechanism. This study reports that Lpd directly binds active Rac (see Drosophila Rac1), which regulates a direct interaction between Lpd and the Scar/WAVE complex via Abi (see Drosophila ABI). Consequently, Lpd controls lamellipodium size, cell migration speed, and persistence via Scar/WAVE in vitro. Moreover, Lpd knockout mice display defective pigmentation because fewer migrating neural crest-derived melanoblasts reach their target during development. Consistently, Lpd regulates mesenchymal neural crest cell migration cell autonomously in Xenopus laevis via the Scar/WAVE complex. Further, Lpd's Drosophila melanogaster orthologue Pico binds Scar, and both regulate collective epithelial border cell migration. Pico also controls directed cell protrusions of border cell clusters in a Scar-dependent manner. Taken together, Lpd is an essential, evolutionary conserved regulator of the Scar/WAVE complex during cell migration in vivo.

Mikami, S., Kanaba, T., Takizawa, N., Kobayashi, A., Maesaki, R., Fujiwara, T., Ito, Y. and Mishima, M. (2013). Structural Insights into the Recruitment of SMRT by the Corepressor SHARP under Phosphorylative Regulation. Structure. PubMed ID: 24268649
Summary: The transcriptional corepressors SMRT/NCoR (see Drosophila Smrter), components of histone deacetylase complexes, interact with nuclear receptors and many other transcription factors. SMRT is a target for the ubiquitously expressed protein kinase CK2 (See Drosophila CK2), which is known to phosphorylate a wide variety of substrates. Increasing evidence suggests that CK2 plays a regulatory role in many cellular events, particularly, in transcription. However, little is known about the precise mode of action involved. This study reports the three-dimensional structure of a SMRT/HDAC1-associated repressor protein (SHARP) in complex with phosphorylated SMRT, as determined by solution NMR. Phosphorylation of the CK2 site on SMRT significantly increased affinity for SHARP. The significance of CK2 phosphorylation was confirmed by reporter assay, and a mechanism involving the process of phosphorylation acting as a molecular switch is proposed Finally, it is proposed that the SPOC domain functions as a phosphorylation binding module.

Friday, December 20th

Bai, H., Kang, P., Hernandez, A. M. and Tatar, M. (2013). Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila. PLoS Genet 9: e1003941. PubMed ID: 24244197
Summary: Reduced insulin/IGF signaling increases lifespan in many animals. To understand how insulin/IGF mediates lifespan in Drosophila, chromatin immunoprecipitation-sequencing analysis was performed with the insulin/IGF regulated transcription factor dFOXO in long-lived insulin/IGF signaling genotypes. Dawdle, an Activin ligand, is bound and repressed by dFOXO when reduced insulin/IGF extends lifespan. Reduced Activin signaling improves performance and protein homeostasis in muscles of aged flies. Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan. These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.

Lee, D. M. and Harris, T. J. (2013). An Arf-GEF Regulates Antagonism between Endocytosis and the Cytoskeleton for Drosophila Blastoderm Development. Curr Biol 23: 2110-2120. PubMed ID: 24120639
Summary: Actin cytoskeletal networks push and pull the plasma membrane (PM) to control cell structure and behavior. Endocytosis also regulates the PM and can be promoted or inhibited by cytoskeletal networks. However, endocytic regulation of the general membrane cytoskeleton is undocumented. This study provides evidence for endocytic inhibition of actomyosin networks. Specifically, Steppke, a cytohesin Arf-guanine nucleotide exchange factor (GEF), was found to control initial PM furrow ingression during the syncytial nuclear divisions and cellularization of the Drosophila embryo. Acting at the tips of ingressing furrows, Steppke promotes local endocytic events through its Arf-GEF activity and in cooperation with the AP-2 clathrin adaptor complex. These Steppke activities appear to reduce local Rho1 protein levels and ultimately restrain actomyosin networks. Without Steppke, Rho1 pathways linked to actin polymerization and myosin activation abnormally expand the membrane cytoskeleton into taut sheets emanating perpendicularly from the furrow tips. These expansions lead to premature cellularization and abnormal expulsions of nuclei from the forming blastoderm. Finally, consistent with earlier reports, it was also found that actomyosin activity can act reciprocally to inhibit the endocytosis at furrow tips. It is proposed that Steppke-dependent endocytosis keeps the cytoskeleton in check as early PM furrows form. Specifically, a cytohesin Arf-GEF-Arf G protein-AP-2 endocytic axis appears to antagonize Rho1 cytoskeletal pathways to restrain the membrane cytoskeleton. However, as furrows lengthen during cellularization, the cytoskeleton gains strength, blocks the endocytic inhibition, and finally closes off the base of each cell to form the blastoderm.

Thursday, December 19th

Unhavaithaya, Y. and Orr-Weaver, T. L. (2013). Centromere proteins CENP-C and CAL1 functionally interact in meiosis for centromere clustering, pairing, and chromosome segregation. Proc Natl Acad Sci U S A 110: 19878-19883. PubMed ID: 24248385
Summary: Meiotic chromosome segregation involves pairing and segregation of homologous chromosomes in the first division and segregation of sister chromatids in the second division. Although it is known that the centromere and kinetochore are responsible for chromosome movement in meiosis as in mitosis, potential specialized meiotic functions are being uncovered. Centromere pairing early in meiosis I, even between nonhomologous chromosomes, and clustering of centromeres can promote proper homolog associations in meiosis I in yeast, plants, and Drosophila. It was not known, however, whether centromere proteins are required for this clustering. Drosophila mutants for the centromere proteins centromere protein-C (CENP-C) and chromosome alignment 1 (CAL1) were exploited to demonstrate that a functional centromere is needed for centromere clustering and pairing. The cenp-C and cal1 mutations result in C-terminal truncations, removing the domains through which these two proteins interact. The mutants show striking genetic interactions, failing to complement as double heterozygotes, resulting in disrupted centromere clustering and meiotic nondisjunction. The cluster of meiotic centromeres localizes to the nucleolus, and this association requires centromere function. In Drosophila, synaptonemal complex (SC) formation can initiate from the centromere, and the SC is retained at the centromere after it disassembles from the chromosome arms. Although functional CENP-C and CAL1 are dispensable for assembly of the SC, they are required for subsequent retention of the SC at the centromere. These results show that integral centromere proteins are required for nuclear position and intercentromere associations in meiosis.

David, D. J., Wang, Q., Feng, J. J. and Harris, T. J. (2013). Bazooka inhibits aPKC to limit antagonism of actomyosin networks during amnioserosa apical constriction. Development 140: 4719-4729. PubMed ID: 24173807
Summary: Cell shape changes drive tissue morphogenesis during animal development. An important example is the apical cell constriction that initiates tissue internalisation. Apical constriction can occur through a phase of cyclic assembly and disassembly of apicomedial actomyosin networks, followed by stabilisation of these networks. Delayed negative-feedback mechanisms typically underlie cyclic behaviour, but the mechanisms regulating cyclic actomyosin networks remain obscure, as do mechanisms that transform overall network behaviour. This study shows that a known inhibitor of apicomedial actomyosin networks in Drosophila amnioserosa cells, the Par-6-aPKC complex, is recruited to the apicomedial domain by actomyosin networks during dorsal closure of the embryo. This finding establishes an actomyosin-aPKC negative-feedback loop in the system. Additionally, aPKC was found to recruit Bazooka to the apicomedial domain, and phosphorylates Bazooka for a dynamic interaction. Remarkably, stabilising aPKC-Bazooka interactions can inhibit the antagonism of actomyosin by aPKC, suggesting that Bazooka acts as an aPKC inhibitor, and providing a possible mechanism for delaying the actomyosin-aPKC negative-feedback loop. These data also implicate an increasing degree of Par-6-aPKC-Bazooka interactions as dorsal closure progresses, potentially explaining a developmental transition in actomyosin behaviour from cyclic to persistent networks. This later impact of aPKC inhibition is supported by mathematical modelling of the system. Overall, this work illustrates how shifting chemical signals can tune actomyosin network behaviour during development.

Wednesday, December 18th


Kim, T. S., Park, J. E., Shukla, A., Choi, S., Murugan, R. N., Lee, J. H., Ahn, M., Rhee, K., Bang, J. K., Kim, B. Y., Loncarek, J., Erikson, R. L. and Lee, K. S. (2013). Hierarchical recruitment of Plk4 and regulation of centriole biogenesis by two centrosomal scaffolds, Cep192 and Cep152. Proc Natl Acad Sci U S A 110: E4849-4857. PubMed ID: 24277814
Summary: Centrosomes play an important role in various cellular processes, including spindle formation and chromosome segregation. They are composed of two orthogonally arranged centrioles, whose duplication occurs only once per cell cycle. Accurate control of centriole numbers is essential for the maintenance of genomic integrity. Although it is well appreciated that polo-like kinase 4 (Plk4; Drosophila Sak kinase) plays a central role in centriole biogenesis, how it is recruited to centrosomes and whether this step is necessary for centriole biogenesis remain largely elusive. This study showed that Plk4 localizes to distinct subcentrosomal regions in a temporally and spatially regulated manner, and that Cep192 and Cep152 serve as two distinct scaffolds that recruit Plk4 to centrosomes in a hierarchical order. Interestingly, Cep192 and Cep152 competitively interacted with the cryptic polo box of Plk4 through their homologous N-terminal sequences containing acidic-alpha-helix and N/Q-rich motifs. Consistent with these observations, the expression of either one of these N-terminal fragments was sufficient to delocalize Plk4 from centrosomes. Furthermore, loss of the Cep192- or Cep152-dependent interaction with Plk4 resulted in impaired centriole duplication that led to delayed cell proliferation. Thus, the spatiotemporal regulation of Plk4 localization by two hierarchical scaffolds, Cep192 and Cep152, is critical for centriole biogenesis.

Cunha-Ferreira, I., Bento, I., Pimenta-Marques, A., Jana, S. C., Lince-Faria, M., Duarte, P., Borrego-Pinto, J., Gilberto, S., Amado, T., Brito, D., Rodrigues-Martins, A., Debski, J., Dzhindzhev, N. and Bettencourt-Dias, M. (2013). Regulation of Autophosphorylation Controls PLK4 Self-Destruction and Centriole Number. Curr Biol 23: 2245-2254. PubMed ID: 24184099
Summary: Polo-like kinase 4 (PLK4) is a major player in centriole biogenesis: in its absence centrioles fail to form, while in excess leads to centriole amplification. The SCF-Slimb/betaTrCP-E3 ubiquitin ligase controls PLK4 levels through recognition of a conserved phosphodegron. SCF-Slimb/betaTrCP substrate binding and targeting for degradation is normally regulated by phosphorylation cascades, controlling complex processes, such as circadian clocks and morphogenesis. This study shows that PLK4 is a suicide kinase, autophosphorylating in residues that are critical for SCF-Slimb/betaTrCP binding. A multisite trans-autophosphorylation mechanism, likely to ensure that both a threshold of PLK4 concentration is attained, is demonstrated, and a sequence of events is observed before PLK4 can autodestruct. It was shown that PLK4 trans-autophosphorylates other PLK4 molecules on both Ser293 and Thr297 within the degron and that these residues contribute differently for PLK4 degradation, the first being critical and the second maximizing auto-destruction. Second, PLK4 trans-autophosphorylates a phospho-cluster outside the degron, which regulates Thr297 phosphorylation, PLK4 degradation, and centriole number. Finally, the importance was shown of PLK4-Slimb/betaTrCP regulation as it operates in both soma and germline. As betaTrCP, PLK4, and centriole number are deregulated in several cancers, this work provides novel links between centriole number control and tumorigenesis.

Tuesday, December 17th

Wang, Y. C., Yang, J. S., Johnston, R., Ren, Q., Luan, H., Brody, T., Odenwald, W. F. and Lee, T. (2013). Drosophila intermediate neural progenitors produce lineage-dependent related series of diverse neurons. Development. PubMed ID: 24306106
Summary: Larval type II neuroblasts (NBs) of the developing adult Drosophila brain, like mammalian neural stem cells, deposit neurons through intermediate neural progenitors (INPs) that can each produce a series of neurons. Both type II NBs and INPs exhibit age-dependent expression of various transcription factors, potentially specifying an array of diverse neurons by combinatorial temporal patterning. Not knowing which mature neurons are made by specific INPs, however, conceals the actual variety of neuron types and limits further molecular studies. This study mapped neurons derived from specific type II NB lineages and found that sibling INPs produced a morphologically similar but temporally regulated series of distinct neuron types. This suggests a common fate diversification program operating within each INP that is modulated by NB age to generate slightly different sets of diverse neurons based on the INP birth order. Analogous mechanisms might underlie the expansion of neuron diversity via INPs in mammalian brain.

Sinsimer, K. S., Lee, J. J., Thiberge, S. Y. and Gavis, E. R. (2013). Germ Plasm Anchoring Is a Dynamic State that Requires Persistent Trafficking. Cell Rep. PubMed ID: 24290763
Summary: Localized cytoplasmic determinants packaged as ribonucleoprotein (RNP) particles direct embryonic patterning and cell fate specification in a wide range of organisms. Once established, the asymmetric distributions of such RNP particles must be maintained, often over considerable developmental time. A striking example is the Drosophila germ plasm, which contains RNP particles whose localization to the posterior of the egg during oogenesis results in their asymmetric inheritance and segregation of germline from somatic fates in the embryo. Although actin-based anchoring mechanisms have been implicated, high-resolution live imaging revealed persistent trafficking of germ plasm RNP particles at the posterior cortex of the Drosophila oocyte. This motility relies on cortical microtubules, is mediated by kinesin and dynein motors, and requires coordination between the microtubule and actin cytoskeletons. Finally, RNP particle motility was shown to be required for long-term germ plasm retention. It is proposed that anchoring is a dynamic state that renders asymmetries robust to developmental time and environmental perturbations.

Monday, December 16th

Gendron, C. M., Kuo, T. H., Harvanek, Z. M., Chung, B. Y., Yew, J. Y., Dierick, H. A. and Pletcher, S. D. (2013). Drosophila Life Span and Physiology Are Modulated by Sexual Perception and Reward. Science. PubMed ID: 24292624
Summary: Sensory perception modulates aging and physiology across taxa. This study found that perception of female sexual pheromones through a specific gustatory receptor, pickpocket 23, expressed in a subset of foreleg neurons in male fruit flies rapidly and reversibly decreases fat stores, reduces resistance to starvation, and limits life span together with neurons that express the reward-mediating neuropeptide F. High-throughput RNA-seq experiments revealed a set of molecular processes that were impacted by the activity of the longevity circuit, thereby identifying new candidate cell non-autonomous aging mechanisms. Mating reversed the effects of pheromone perception, suggesting a model where life span is modulated through integration of sensory and reward circuits and where healthy aging may be compromised when the expectations defined by sensory perception are discordant with ensuing experience.

Hattori, Y., Usui, T., Satoh, D., Moriyama, S., Shimono, K., Itoh, T., Shirahige, K. and Uemura, T. (2013). Sensory-Neuron Subtype-Specific Transcriptional Programs Controlling Dendrite Morphogenesis: Genome-wide Analysis of Abrupt and Knot/Collier. Dev Cell. PubMed ID: 24290980
Summary: The transcription factors Abrupt (Ab) and Knot (Kn) act as selectors of distinct dendritic arbor morphologies in two classes of Drosophila peripheral nervous system sensory neurons, termed class I and class IV, respectively. Binding-site mapping and transcriptional profiling of these isolated neurons were performed in this study. Their profiles were similarly enriched in cell-type-specific enhancers of genes implicated in neural development. A total of 429 target genes were identified, of which 56 were common to Ab and Kn; these targets included genes necessary to shape dendritic arbors in either or both of the two sensory subtypes. Furthermore, a common target gene, encoding the cell adhesion molecule Ten-m, was expressed more strongly in class I than class IV, and this differential was critical to the class-selective directional control of dendritic branch sprouting or extension. These analyses illustrate how differentiating neurons employ distinct and shared repertoires of gene expression to produce class-selective morphological traits.

Sunday, December 15th

Zhang, S. and Roman, G. (2013). Presynaptic inhibition of γ lobe neurons is required for olfactory learning in Drosophila. Curr Biol. PubMed ID: 24291093
Summary: The loss of heterotrimeric Go signaling through the expression of pertussis toxin (PTX) within either the α/β or γ lobe mushroom body neurons of Drosophila results in the impaired aversive olfactory associative memory formation. This study focused on the cellular effects of Go signaling in the γ lobe mushroom body neurons during memory formation. Expression of PTX in the γ lobes specifically inhibits Go activation, leading to poor olfactory learning and an increase in odor-elicited synaptic vesicle release. In the γ lobe neurons, training decreases synaptic vesicle release elicited by the unpaired conditioned stimulus -, while leaving presynaptic activation by the paired conditioned stimulus + unchanged. PTX expression in γ lobe neurons inhibits the generation of this differential synaptic activation by conditioned stimuli after negative reinforcement. Hyperpolarization of the γ lobe neurons or the inhibition of presynaptic activity through the expression of dominant negative dynamin transgenes ameliorated the memory impairment caused by PTX, indicating that the disinhibition of these neurons by PTX was responsible for the poor memory formation. The role for γ lobe inhibition, carried out by Go activation, indicates that an inhibitory circuit involving these neurons plays a positive role in memory acquisition. This newly uncovered requirement for inhibition of odor-elicited activity within the γ lobes is consistent with these neurons serving as comparators during learning, perhaps as part of an odor salience modification mechanism.

Gruntman, E. and Turner, G. C. (2013). Integration of the olfactory code across dendritic claws of single mushroom body neurons. Nat Neurosci 16: 1821-1829. PubMed ID: 24141312
Summary: In the olfactory system, sensory inputs are arranged in different glomerular channels, which respond in combinatorial ensembles to the various chemical features of an odor. This study investigated where and how this combinatorial code is read out deeper in the brain. The unique morphology was exploited of neurons in the Drosophila mushroom body, which receive input on large dendritic claws. Imaging odor responses of these dendritic claws revealed that input channels with distinct odor tuning converge on individual mushroom body neurons. How these inputs interact to drive the cell to spike threshold was investigated using intracellular recordings to examine mushroom body responses to optogenetically controlled input. The results provide an elegant explanation for the characteristic selectivity of mushroom body neurons: these cells receive different types of input and require those inputs to be coactive to spike. These results establish the mushroom body as an important site of integration in the fly olfactory system.

Saturday, December 14

Turek, M., Lewandrowski, I. and Bringmann, H. (2013). An AP2 Transcription Factor Is Required for a Sleep-Active Neuron to Induce Sleep-like Quiescence in C. elegans. Curr Biol 23: 2215-2223. PubMed ID: 24184105
Summary: Sleep is an essential behavior (see Drosophila behavioral paradigms) that is found in all animals that have a nervous system. Neural activity is thought to control sleep, but little is known about the identity and the function of neural circuits underlying sleep. Lethargus is a developmentally regulated period of behavioral quiescence in C. elegans larvae that has sleep-like properties. Sleep-like behavior in C. elegans larvae was found to require a highly conserved AP2 transcription factor, aptf-1 (see Drosophila AP-2), which was expressed strongly in only five interneurons in the head. Expression of aptf-1 in one of these neurons, the GABAergic neuron RIS, was required for quiescence. RIS was strongly and acutely activated at the transition from wake-like to sleep-like behavior. Optogenetic activation of aptf-1-expressing neurons ectopically induced acute behavioral quiescence in an aptf-1-dependent manner. RIS ablation caused a dramatic reduction of quiescence. RIS-dependent quiescence, however, does not require GABA but requires neuropeptide signaling. It is concluded that RIS acts as a sleep-active, sleep-promoting neuron that requires aptf-1 to induce sleep-like behavior through neuropeptide signaling. Sleep-promoting GABAergic-peptidergic neurons have also been identified in vertebrate brains, suggesting that common circuit principles exist between sleep in vertebrates and sleep-like behavior in invertebrates.

Ambrus, A. M., Islam, A. B., Holmes, K. B., Moon, N. S., Lopez-Bigas, N., Benevolenskaya, E. V. and Frolov, M. V. (2013). Loss of dE2F Compromises Mitochondrial Function. Dev Cell 27: 438-451. PubMed ID: 24286825
Summary: E2F/DP transcription factors regulate cell proliferation and apoptosis. This study investigated the mechanism of the resistance of Drosophila dDP mutants to irradiation-induced apoptosis. Contrary to the prevailing view, this is not due to an inability to induce the apoptotic transcriptional program, because this program was shown to be induced; rather, the inability is due to a mitochondrial dysfunction of dDP mutants. This defect is attributed to E2F/DP-dependent control of expression of mitochondria-associated genes. Genetic attenuation of several of these E2F/DP targets mimics the dDP mutant mitochondrial phenotype and protects against irradiation-induced apoptosis. Significantly, the role of E2F/DP in the regulation of mitochondrial function is conserved between flies and humans. Thus, these results uncover a role of E2F/DP in the regulation of mitochondrial function and demonstrate that this aspect of E2F regulation is critical for the normal induction of apoptosis in response to irradiation.

Friday, December 13th

Kim, W. J., Jan, L. Y. and Jan, Y. N. (2013). A PDF/NPF Neuropeptide Signaling Circuitry of Male Drosophila melanogaster Controls Rival-Induced Prolonged Mating. Neuron 80: 1190-1205. PubMed ID: 24314729
Summary: A primary function of males for many species involves mating with females for reproduction. Drosophila melanogaster males respond to the presence of other males by prolonging mating duration to increase the chance of passing on their genes. To understand the basis of such complex behaviors, this study examined the genetic network and neural circuits that regulate rival-induced Longer-Mating-Duration (LMD). This study identified a small subset of clock neurons in the male brain that regulate LMD via neuropeptide signaling. LMD requires the function of pigment-dispersing factor (PDF) in four s-LNv neurons and its receptor PDFR in two LNd neurons per hemisphere, as well as the function of neuropeptide F (NPF) in two neurons within the sexually dimorphic LNd region and its receptor NPFR1 in four s-LNv neurons per hemisphere. Moreover, rival exposure modifies the neuronal activities of a subset of clock neurons involved in neuropeptide signaling for LMD.

Zhou, Q., Ellison, C. E., Kaiser, V. B., Alekseyenko, A. A., Gorchakov, A. A. and Bachtrog, D. (2013). The epigenome of evolving Drosophila neo-sex chromosomes: dosage compensation and heterochromatin formation. PLoS Biol 11: e1001711. PubMed ID: 24265597
Summary: Sex chromosomes originated from autosomes but have evolved a highly specialized chromatin structure. Drosophila Y chromosomes are composed entirely of silent heterochromatin, while male X chromosomes have highly accessible chromatin and are hypertranscribed as a result of dosage compensation. This study dissected the molecular mechanisms and functional pressures driving heterochromatin formation and dosage compensation of the recently formed neo-sex chromosomes of Drosophila miranda. The onset of heterochromatin formation on the neo-Y is triggered by an accumulation of repetitive DNA. The neo-X has evolved partial dosage compensation and it was found that diverse mutational paths have been utilized to establish several dozen novel binding consensus motifs for the dosage compensation complex on the neo-X, including simple point mutations at pre-binding sites, insertion and deletion mutations, microsatellite expansions, or tandem amplification of weak binding sites. Spreading of these silencing or activating chromatin modifications to adjacent regions results in massive mis-expression of neo-sex linked genes, and little correspondence between functionality of genes and their silencing on the neo-Y or dosage compensation on the neo-X. Intriguingly, the genomic regions being targeted by the dosage compensation complex on the neo-X and those becoming heterochromatic on the neo-Y show little overlap, possibly reflecting different propensities along the ancestral chromosome that formed the sex chromosome to adopt active or repressive chromatin configurations. These findings have broad implications for current models of sex chromosome evolution, and demonstrate how mechanistic constraints can limit evolutionary adaptations. The study also highlights how evolution can follow predictable genetic trajectories, by repeatedly acquiring the same 21-bp consensus motif for recruitment of the dosage compensation complex, yet utilizing a diverse array of random mutational changes to attain the same phenotypic outcome.

Schnaitmann, C., Garbers, C., Wachtler, T. and Tanimoto, H. (2013). Color Discrimination with Broadband Photoreceptors. Curr Biol. PubMed ID: 24268411
Summary: Color vision is commonly assumed to rely on photoreceptors tuned to narrow spectral ranges. In the ommatidium of Drosophila, the four types of so-called inner photoreceptors express different narrow-band opsins. In contrast, the outer photoreceptors have a broadband spectral sensitivity and were thought to exclusively mediate achromatic vision. Using computational models and behavioral experiments, this study demonstrated that the broadband outer photoreceptors contribute to color vision in Drosophila. The model of opponent processing that includes the opsin of the outer photoreceptors scored the best fit to wavelength discrimination data. To experimentally uncover the contribution of individual photoreceptor types, phototransduction of targeted photoreceptor combinations were restored in a blind mutant. Dichromatic flies with only broadband photoreceptors and one additional receptor type can discriminate different colors, indicating the existence of a specific output comparison of the outer and inner photoreceptors. Furthermore, blocking interneurons postsynaptic to the outer photoreceptors specifically impaired color but not intensity discrimination. These findings show that receptors with a complex and broad spectral sensitivity can contribute to color vision and reveal that chromatic and achromatic circuits in the fly share common photoreceptors.

Thursday, December 12th

Janisch, K. M., Vock, V. M., Fleming, M. S., Shrestha, A., Grimsley-Myers, C. M., Rasoul, B. A., Neale, S. A., Cupp, T. D., Kinchen, J. M., Liem, K. F., Jr. and Dwyer, N. D. (2013). The vertebrate-specific Kinesin-6, Kif20b, is required for normal cytokinesis of polarized cortical stem cells and cerebral cortex size. Development 140: 4672-4682. PubMed ID: 24173802
Summary: Mammalian neuroepithelial stem cells divide using a polarized form of cytokinesis, which is not well understood. The cytokinetic furrow cleaves the cell by ingressing from basal to apical, forming the midbody at the apical membrane. The midbody mediates abscission by recruiting many factors, including the Kinesin-6 family member Kif20b (Drosophila homolog: Subito). In developing embryos, Kif20b mRNA is most highly expressed in neural stem/progenitor cells. A loss-of-function mutant in Kif20b, magoo, was found in a forward genetic screen. magoo has a small cerebral cortex, with reduced production of progenitors and neurons, but preserved layering. In contrast to other microcephalic mouse mutants, mitosis and cleavage furrows of cortical stem cells appear normal in magoo. However, apical midbodies show changes in number, shape and positioning relative to the apical membrane. Interestingly, the disruption of abscission does not appear to result in binucleate cells, but in apoptosis. Thus, Kif20b is required for proper midbody organization and abscission in polarized cortical stem cells and has a crucial role in the regulation of cerebral cortex growth.

Lewis, M., Arnot, C. J., Beeston, H., McCoy, A., Ashcroft, A. E., Gay, N. J. and Gangloff, M. (2013). Cytokine Spatzle binds to the Drosophila immunoreceptor Toll with a neurotrophin-like specificity and couples receptor activation. Proc Natl Acad Sci U S A. PubMed ID: 24282309
Summary: Drosophila Toll functions in embryonic development and innate immunity and is activated by an endogenous ligand, Spatzle (Spz). The related Toll-like receptors in vertebrates also function in immunity but are activated directly by pathogen-associated molecules such as bacterial endotoxin. This study presents the crystal structure at 2.35-Å resolution of dimeric Spz bound to a Toll ectodomain encompassing the first 13 leucine-rich repeats. The cystine knot of Spz binds the concave face of the Toll leucine-rich repeat solenoid in an area delineated by N-linked glycans and induces a conformational change. Mutagenesis studies confirm that the interface observed in the crystal structure is relevant for signaling. The asymmetric binding mode of Spz to Toll is similar to that of nerve growth factor (NGF) in complex with the p75 neurotrophin receptor but is distinct from that of microbial ligands bound to the Toll-like receptors. Overall, this study indicates an allosteric signaling mechanism for Toll in which ligand binding to the N terminus induces a conformational change that couples to homodimerization of juxtamembrane structures in the Toll ectodomain C terminus.

Livigni, A., Peradziryi, H., Sharov, A. A., Chia, G., Hammachi, F., Migueles, R. P., Sukparangsi, W., Pernagallo, S., Bradley, M., Nichols, J., Ko, M. S. and Brickman, J. M. (2013). A Conserved Oct4/POUV-Dependent Network Links Adhesion and Migration to Progenitor Maintenance. Curr Biol 23: 2233-2244. PubMed ID: 24210613
Summary: The class V POU domain transcription factor Oct4 (Pou5f1) is a pivotal regulator of embryonic stem cell (ESC) self-renewal and reprogramming of somatic cells to induced pluripotent stem (iPS) cells. Oct4 is also an important evolutionarily conserved regulator of progenitor cell differentiation during embryonic development. This study examined the function of Oct4 homologs in Xenopus embryos and compare this to the role of Oct4 in maintaining mammalian embryo-derived stem cells. Based on a combination of expression profiling of Oct4/POUV-depleted Xenopus embryos and in silico analysis of existing mammalian Oct4 target data sets, a set of evolutionary-conserved Oct4/POUV targets was defined. Most of these targets are regulators of cell adhesion. This is consistent with Oct4/POUV phenotypes observed in the adherens junctions in Xenopus ectoderm, mouse embryonic, and epiblast stem cells. A number of these targets can rescue both Oct4/POUV phenotypes in cellular adhesion and multipotent progenitor cell maintenance, whereas expression of cadherins on their own can only transiently support adhesion and block differentiation in both ESC and Xenopus embryos. Currently, the list of Oct4 transcriptional targets contains thousands of genes. Using evolutionary conservation, a core set of functionally relevant factors was identified that linked the maintenance of adhesion to Oct4/POUV.The regulation of adhesion by the Oct4/POUV network occurs at both transcriptional and posttranslational levels and is required for pluripotency.

Wednesday, December 11th

Li, Q., Ha, T. S., Okuwa, S., Wang, Y., Wang, Q., Millard, S. S., Smith, D. P. and Volkan, P. C. (2013). Combinatorial Rules of Precursor Specification Underlying Olfactory Neuron Diversity. Curr Biol. PubMed ID: 24268416
Summary: Sensory neuron diversity ensures optimal detection of the external world and is a hallmark of sensory systems. An extreme example is the olfactory system, as individual olfactory receptor neurons (ORNs) adopt unique sensory identities by typically expressing a single receptor gene from a large genomic repertoire. In Drosophila, about 50 different ORN classes are generated from a field of precursor cells, giving rise to spatially restricted and distinct clusters of ORNs on the olfactory appendages. Developmental strategies spawning ORN diversity from an initially homogeneous population of precursors are largely unknown. This study has unraveled the nested and binary logic of the combinatorial code that patterns the decision landscape of precursor states underlying ORN diversity in the Drosophila olfactory system. The transcription factor Rotund (Rn) is a critical component of this code that is expressed in a subset of ORN precursors. Addition of Rn to preexisting transcription factors that assign zonal identities to precursors on the antenna subdivides each zone and almost exponentially increases ORN diversity by branching off novel precursor fates from default ones within each zone. In rn mutants, rn-positive ORN classes are converted to rn-negative ones in a zone-specific manner. This study provides a model describing how nested and binary changes in combinations of transcription factors could coordinate and pattern a large number of distinct precursor identities within a population to modulate the level of ORN diversity during development and evolution.

Yang, S., Edman, L. C., Sanchez-Alcaniz, J. A., Fritz, N., Bonilla, S., Hecht, J., Uhlen, P., Pleasure, S. J., Villaescusa, J. C., Marin, O. and Arenas, E. (2013). Cxcl12/Cxcr4 signaling controls the migration and process orientation of A9-A10 dopaminergic neurons. Development 140: 4554-4564. PubMed ID: 24154522
Summary: Chemokine CXCL12 is widely expressed in the central nervous system and acts through its receptor CXCR4 for proper functioning of neural progenitor cells. CXCL12/CXCR4 signaling has been reported to regulate three essential processes for the establishment of neural networks in different neuronal systems: neuronal migration, cell positioning and axon wiring. However, it is not known whether it regulates the development of A9-A10 tyrosine hydroxylase positive (TH+) midbrain dopaminergic (mDA) neurons. This study reports that Cxcl12 is expressed in the meninges surrounding the ventral midbrain (VM), whereas CXCR4 is present in NURR1+ mDA precursors and mDA neurons from E10.5 to E14.5. CXCR4 is activated in NURR1+ cells as they migrate towards the meninges. Accordingly, VM meninges and CXCL12 promoted migration and neuritogenesis of TH+ cells in VM explants in a CXCR4-dependent manner. Moreover, in vivo electroporation of Cxcl12 at E12.5 in the basal plate resulted in lateral migration, whereas expression in the midline resulted in retention of TH+ cells in the IZ close to the midline. Analysis of Cxcr4-/- mice revealed the presence of VM TH+ cells with disoriented processes in the intermediate zone (IZ) at E11.5 and marginal zone (MZ) at E14. Consistently, pharmacological blockade of CXCR4 or genetic deletion of Cxcr4 resulted in an accumulation of TH+ cells in the lateral aspect of the IZ at E14, indicating that CXCR4 is required for the radial migration of mDA neurons in vivo. Altogether, these findings demonstrate that CXCL12/CXCR4 regulates the migration and orientation of processes in A9-A10 mDA neurons.

Osorio, C., Chacon, P. J., Kisiswa, L., White, M., Wyatt, S., Rodriguez-Tebar, A. and Davies, A. M. (2013). Growth differentiation factor 5 is a key physiological regulator of dendrite growth during development. . Development 140: 4751-4762. PubMed ID: 24173804
Summary: Dendrite size and morphology are key determinants of the functional properties of neurons. This study shows that growth differentiation factor 5 (GDF5), a member of the bone morphogenetic protein (BMP) subclass of the transforming growth factor beta superfamily with a well-characterised role in limb morphogenesis, is a key regulator of the growth and elaboration of pyramidal cell dendrites in the developing hippocampus. Pyramidal cells co-express GDF5 and its preferred receptors, BMP receptor 1B and BMP receptor 2, during development. In culture, GDF5 substantially increased dendrite, but not axon, elongation from these neurons by a mechanism that depends on activation of SMADs 1/5/8 and upregulation of the transcription factor HES5. In vivo, the apical and basal dendritic arbours of pyramidal cells throughout the hippocampus were markedly stunted in both homozygous and heterozygous Gdf5 null mutants, indicating that dendrite size and complexity are exquisitely sensitive to the level of endogenous GDF5 synthesis.

Tuesday, December 10th

Chak, K. and Kolodkin, A. L. (2013). Function of the Drosophila receptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance. Development. PubMed ID: 24284209
Summary: The second messengers cAMP and cGMP modulate attraction and repulsion mediated by neuronal guidance cues. This study found that the Drosophila receptor guanylyl cyclase Gyc76C genetically interacts with Semaphorin 1a (Sema-1a) and physically associates with the Sema-1a receptor Plexin A (PlexA). PlexA regulates Gyc76C catalytic activity in vitro, and each distinct Gyc76C protein domain is crucial for regulating Gyc76C activity in vitro and motor axon guidance in vivo. The cytosolic protein dGIPC interacts with Gyc76C and facilitates Sema-1a-PlexA/Gyc76C-mediated motor axon guidance. These findings provide an in vivo link between semaphorin-mediated repulsive axon guidance and alteration of intracellular neuronal cGMP levels.

Moeller, M. E., Danielsen, E. T., Herder, R., O'Connor, M. B. and Rewitz, K. F. (2013). Dynamic feedback circuits function as a switch for shaping a maturation-inducing steroid pulse in Drosophila. Development 140: 4730-4739. PubMed ID: 24173800
Summary: Steroid hormones trigger the onset of sexual maturation in animals by initiating genetic response programs that are determined by steroid pulse frequency, amplitude and duration. Although steroid pulses coordinate growth and timing of maturation during development, the mechanisms generating these pulses are not known. This study shows that the ecdysone steroid pulse that drives the juvenile-adult transition in Drosophila is determined by feedback circuits in the prothoracic gland (PG), the major steroid-producing tissue of insect larvae. These circuits coordinate the activation and repression of hormone synthesis, the two key parameters determining pulse shape (amplitude and duration). Ecdysone has a positive-feedback effect on the PG, rapidly amplifying its own synthesis to trigger pupariation as the onset of maturation. During the prepupal stage, a negative-feedback signal ensures the decline in ecdysone levels required to produce a temporal steroid pulse that drives developmental progression to adulthood. The feedback circuits rely on a developmental switch in the expression of Broad isoforms that transcriptionally activate or silence components in the ecdysone biosynthetic pathway. Remarkably, this study shows that the same well-defined genetic program that stimulates a systemic downstream response to ecdysone is also utilized upstream to set the duration and amplitude of the ecdysone pulse. Activation of this switch-like mechanism ensures a rapid, self-limiting PG response that functions in producing steroid oscillations that can guide the decision to terminate growth and promote maturation.

Thomas, C. and Strutt, D. (2014). Rabaptin-5 and Rabex-5 are neoplastic tumour suppressor genes that interact to modulate Rab5 dynamics in Drosophila melanogaster. Dev Biol. 385(1): 107-21 PubMed ID: 24104056
Summary: Endocytosis plays an important role in the regulation of tumour growth and metastasis. In Drosophila, a number of endocytic neoplastic tumour suppressor genes have been identified that when mutated cause epithelial disruption and over-proliferation. This study characterises the Drosophila homologue of the Rab5 effector Rabaptin-5, and shows that it is a novel neoplastic tumour suppressor. Its ability to bind Rab5 and modulate early endosomal dynamics is conserved in Drosophila, as is its interaction with the Rab5 GEF Rabex5, for which neoplastic tumour suppressor characteristics were also demonstrated. Surprisingly, disruption of apico-basal polarity is not disrupted in Rabaptin-5 and Rabex-5 mutant tissues; instead the tumour phenotype is associated with upregulation of Jun N-terminal Kinase (JNK) and JAK)/STAT signalling.

Monday, December 9th

Zhao, Y., Flandin, P., Vogt, D., Blood, A., Hermesz, E., Westphal, H. and J, L. R. R. (2014). Ldb1 is essential for development of Nkx2.1 lineage derived GABAergic and cholinergic neurons in the telencephalon. Dev Biol 385: 94-106. PubMed ID: 24157949
Summary: The progenitor zones of the embryonic mouse ventral telencephalon give rise to GABAergic and cholinergic neurons. Two LIM-homeodomain (LIM-HD) transcription factors, Lhx6 and Lhx8, that are downstream of Nkx2.1 (related to Drosophila Vnd), are critical for the development of telencephalic GABAergic and cholinergic neurons. This study investigated the role of Ldb1 (Drosophila homolog Chip), a nuclear protein that binds directly to all LIM-HD factors, in the development of these ventral telencephalon derived neurons. Ldb1 is expressed in the Nkx2.1 cell lineage during embryonic development and in mature neurons. Conditional deletion of Ldb1 causes defects in the expression of a series of genes in the ventral telencephalon and severe impairment in the tangential migration of cortical interneurons from the ventral telencephalon. Similar to the phenotypes observed in Lhx6 or Lhx8 mutant mice, the Ldb1 conditional mutants show a reduction in the number of both GABAergic and cholinergic neurons in the telencephalon. Furthermore, this analysis reveals defects in the development of the parvalbumin-positive neurons in the globus pallidus and striatum of the Ldb1 mutants. These results provide evidence that Ldb1 plays an essential role as a transcription co-regulator of Lhx6 and Lhx8 in the control of mammalian telencephalon development.

Spracklen, A. J., Kelpsch, D. J., Chen, X., Spracklen, C. N. and Tootle, T. L. (2013). Prostaglandins temporally regulate cytoplasmic actin bundle formation during Drosophila oogenesis. Mol Biol Cell. PubMed ID: 24284900
Summary: While Prostaglandins (PGs), lipid signals produced downstream of cyclooxygenase (COX) enzymes, regulate actin dynamics in cell culture and platelets, their roles during development are largely unknown. This study definee a new role for Pxt, the Drosophila COX-like enzyme, in regulating the actin cytoskeleton-temporal restriction of actin remodeling during oogenesis. PGs are required for actin filament bundle formation during stage 10B (S10B). Additionally, loss of Pxt results in early actin remodeling, including extensive actin filaments and aggregates, within the posterior nurse cells of stage 9 (S9) follicles; wild-type follicles exhibit similar structures at a low frequency. Hu li tai shao (Hts), the homolog of Adducin, and Villin (Quail), an actin bundler, localize to all early actin structures, while Enabled (Ena), an actin elongation factor, preferentially localizes to those in pxt mutants. Reduced Ena levels strongly suppress early actin remodeling in pxt mutants. Furthermore, loss of Pxt results in reduced Ena localization to the sites of bundle formation during S10B. Together these data lead to the model that PGs temporally regulate actin remodeling during Drosophila oogenesis by controlling Ena localization/activity, such that in S9, PG signaling inhibits, while at S10B, it promotes Ena-dependent actin remodeling.

Sakaue-Sawano, A., Hoshida, T., Yo, M., Takahashi, R., Ohtawa, K., Arai, T., Takahashi, E., Noda, S., Miyoshi, H. and Miyawaki, A. (2013). Visualizing developmentally programmed endoreplication in mammals using ubiquitin oscillators. Development 140: 4624-4632. PubMed ID: 24154524
Summary: The majority of mammalian somatic cells maintain a diploid genome. However, some mammalian cell types undergo multiple rounds of genome replication (endoreplication) as part of normal development and differentiation. For example, trophoblast giant cells (TGCs) in the placenta become polyploid through endoreduplication (bypassed mitosis), and megakaryocytes (MKCs) in the bone marrow become polyploid through endomitosis (abortive mitosis). During the normal mitotic cell cycle, geminin and Cdt1 are involved in 'licensing' of replication origins, which ensures that replication occurs only once in a cell cycle. Their protein accumulation is directly regulated by two E3 ubiquitin ligase activities, APC(Cdh1), homolog of Drosophila Fizzy related, and SCF(Skp2) (see Drosophila Skp2), which oscillate reciprocally during the cell cycle. Although proteolysis-mediated, oscillatory accumulation of proteins has been documented in endoreplicating Drosophila cells, it is not known whether the ubiquitin oscillators that control normal cell cycle transitions also function during mammalian endoreplication. In this study, transgenic mice were used expressing Fucci fluorescent cell-cycle probes that report the activity of APC(Cdh1) and SCF(Skp2). By performing long-term, high temporal-resolution Fucci imaging, it was possible to visualize reciprocal activation of APC(Cdh1) and SCF(Skp2) in differentiating TGCs and MKCs grown in custom-designed culture wells. TGCs and MKCs were found to both skip cytokinesis, but in different ways, and that the reciprocal activation of the ubiquitin oscillators in MKCs varies with the polyploidy level. Three-dimensional reconstructions were obtained of highly polyploid TGCs in whole, fixed mouse placentas. Thus, the Fucci technique is able to reveal the spatiotemporal regulation of the endoreplicative cell cycle during differentiation.

Sunday, December 8th

Fleming, J. T., He, W., Hao, C., Ketova, T., Pan, F. C., Wright, C. C., Litingtung, Y. and Chiang, C. (2013). The purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors. Dev Cell 27: 278-292. PubMed ID: 24229643
Summary: The prospective white matter (PWM) in the nascent cerebellum contains a transient germinal compartment that produces all postnatally born GABAergic inhibitory interneurons and astrocytes. However, little is known about the molecular identity and developmental potential of resident progenitors or key regulatory niche signals. This study show that neural stem-cell-like primary progenitors (TncYFP-low CD133+) generate intermediate astrocyte (TncYFP-low CD15+) precursors and GABAergic transient amplifying (Ptf1a+) cells. Interestingly, these lineally related but functionally divergent progenitors commonly respond to Sonic hedgehog (Shh; Drosophila homolog, Hedgehog), and blockade of reception in TNCYFP-low cells attenuates proliferation in the PWM, reducing both intermediate progenitor classes. Furthermore, Shh produced from distant Purkinje neurons maintains the PWM niche independently of its classical role in regulating granule cell precursor proliferation. These results indicate that Purkinje neurons maintain a bidirectional signaling axis, driving the production of spatially and functionally opposed inhibitory and excitatory interneurons important for motor learning and cognition.

Brzezinski, J. A. t., Uoon Park, K. and Reh, T. A. (2013). Blimp1 (Prdm1) prevents re-specification of photoreceptors into retinal bipolar cells by restricting competence. Dev Biol 384: 194-204. PubMed ID: 24125957
Summary: During retinal development, photoreceptors and bipolar cells express the transcription factor Otx2 (Drosophila homolog: Orthodenticle). Blimp1 is transiently expressed in Otx2+ cells. Blimp1 deletion results in excess bipolar cell formation at the expense of photoreceptors. In principle, Blimp1 could be expressed only in Otx2+ cells that are committed to photoreceptor fate. Alternatively, Blimp1 could be expressed broadly in Otx2+ cells and silenced to allow bipolar cell development. To distinguish between these alternatives, the fate of Blimp1 expressing cells was followed using Blimp1-Cre mice and Lox-Stop-Lox reporter strains. Blimp1+ cells were observed to give rise to all photoreceptors, but also to one third of bipolar cells, consistent with the latter alternative: that Blimp1 inhibits bipolar competence in Otx2+ cells and must be silenced to allow bipolar cell generation. To further test this hypothesis, transitioning rod photoreceptors were looked for in Blimp1 conditional knock-out (CKO) mice carrying the NRL-GFP transgene, which specifically labels rods. Control animals lacked NRL-GFP+ bipolar cells. In contrast, about half of the precociously generated bipolar cells in Blimp1 CKO mice co-expressed GFP, suggesting that rods become re-specified as bipolar cells. Birthdating analyses in control and Blimp1 CKO mice showed that bipolar cells were birthdated as early as E13.5 in Blimp1 CKO mice, five days before this cell type was generated in the wild-type retina. Taken together, these data suggest that early Otx2+ cells upregulate photoreceptor and bipolar genes, existing in a bistable state. Blimp1 likely forms a cross-repressive network with pro-bipolar factors such that the winner of this interaction stabilizes the photoreceptor or bipolar state, respectively.

Ruf, V., Holzem, C., Peyman, T., Walz, G., Blackwell, T. K. and Neumann-Haefelin, E. (2013). TORC2 signaling antagonizes SKN-1 to induce C. elegans mesendodermal embryonic development. Dev Biol 384: 214-227. PubMed ID: 23973804
Summary: The evolutionarily conserved target of rapamycin (TOR) kinase controls fundamental metabolic processes to support cell and tissue growth. TOR functions within the context of two distinct complexes, TORC1 and TORC2. TORC2, with its specific component Rictor, has been recently implicated in aging and regulation of growth and metabolism. This study identified rict-1/Rictor (homolog of Drosophila Rictor) as a regulator of embryonic development in C. elegans. The transcription factor skn-1 (homolog of Drosophila cap'n'collar) establishes development of the mesendoderm in embryos, and is required for cellular homeostasis and longevity in adults. Loss of maternal skn-1 function leads to mis-specification of the mesendodermal precursor and failure to form intestine and pharynx. Genetic inactivation of rict-1 suppressed skn-1-associated lethality by restoring mesendodermal specification in skn-1 deficient embryos. Inactivation of other TORC2 but not TORC1 components also partially rescues skn-1 embryonic lethality. The SGK-1 kinase (homolog of the vertebate serum- and glucocorticoid-inducible kinase SGK) mediates these functions downstream of rict-1/TORC2, as a sgk-1 gain-of-function mutant suppresses the rict-1 mutant phenotype. These data indicate that TORC2 and SGK-1 antagonize SKN-1 during embryonic development.

Saturday, December 7th

Dragojlovic-Munther, M. and Martinez-Agosto, J. A. (2013). Extracellular matrix-modulated Heartless signaling in Drosophila blood progenitors regulates their differentiation via a Ras/ETS/FOG pathway and target of rapamycin function. Dev Biol 384: 313-330. PubMed ID: 23603494
Summary: Maintenance of hematopoietic progenitors ensures a continuous supply of blood cells during the lifespan of an organism. Thus, understanding the molecular basis for progenitor maintenance is a continued focus of investigation. A large pool of undifferentiated blood progenitors are maintained in the Drosophila hematopoietic organ, the larval lymph gland, by a complex network of signaling pathways that are mediated by niche-, progenitor-, or differentiated hemocyte-derived signals. This study examined the function of the Drosophila fibroblast growth factor receptor (FGFR), Heartless, a critical regulator of early lymph gland progenitor specification in the late embryo, during larval lymph gland hematopoiesis. Activation of Heartless signaling in hemocyte progenitors by its two ligands, Pyramus and Thisbe, is both required and sufficient to induce progenitor differentiation and formation of the plasmatocyte-rich lymph gland cortical zone. Two transcriptional regulators were identified that function downstream of Heartless signaling in lymph gland progenitors, the ETS protein, Pointed, and the Friend-of-GATA (FOG) protein, U-shaped, which are required for this Heartless-induced differentiation response. Furthermore, cross-talk of Heartless and target of rapamycin signaling in hemocyte progenitors is required for lamellocyte differentiation downstream of Thisbe-mediated Heartless activation. Finally, the Drosophila heparan sulfate proteoglycan, Trol, was identified as a critical negative regulator of Heartless ligand signaling in the lymph gland, demonstrating that sequestration of differentiation signals by the extracellular matrix is a unique mechanism employed in blood progenitor maintenance that is of potential relevance to many other stem cell niches.

Grigorian, M., Liu, T., Banerjee, U. and Hartenstein, V. (2013). The proteoglycan Trol controls the architecture of the extracellular matrix and balances proliferation and differentiation of blood progenitors in the Drosophila lymph gland. Dev Biol 384: 301-312. PubMed ID: 23510717
Summary: The heparin sulfate proteoglycan Terribly Reduced Optic Lobes (Trol) is the Drosophila melanogaster homolog of the vertebrate protein Perlecan. Trol is expressed as part of the extracellular matrix (ECM) found in the hematopoietic organ, called the lymph gland. In the normal lymph gland, the ECM forms thin basement membranes around individual or small groups of blood progenitors. The pattern of basement membranes, reported by Trol expression, is spatio-temporally correlated to hematopoiesis. The central, medullary zone which contain undifferentiated hematopoietic progenitors has many, closely spaced membranes. Fewer basement membranes are present in the outer, cortical zone, where differentiation of blood cells takes place. Loss of trol causes a dramatic change of the ECM into a three-dimensional, spongy mass that fills wide spaces scattered throughout the lymph gland. At the same time proliferation is reduced, leading to a significantly smaller lymph gland. Interestingly, differentiation of blood progenitors in trol mutants is precocious, resulting in the break-down of the usual zonation of the lymph gland. which normally consists of an immature center (medullary zone) where cells remain undifferentiated, and an outer cortical zone, where differentiation sets in. Evidence is presented that the effect of Trol on blood cell differentiation is mediated by Hedgehog (Hh) signaling, which is known to be required to maintain an immature medullary zone. Overexpression of hh in the background of a trol mutation is able to rescue the premature differentiation phenotype. These data provide novel insight into the role of the ECM component Perlecan during Drosophila hematopoiesis.

Manhire-Heath, R., Golenkina, S., Saint, R. and Murray, M. J. (2013). Netrin-dependent downregulation of Frazzled/DCC is required for the dissociation of the peripodial epithelium in Drosophila. Nat Commun 4: 2790. PubMed ID: 24225841
Summary: Netrins are secreted chemoattractants with roles in axon guidance, cell migration and epithelial plasticity. Netrin-1 also promotes the survival of metastasized cells by inhibiting the pro-apoptotic effects of its receptor Deleted in Colorectal Carcinoma (DCC). This study reports that Netrins can also regulate epithelial dissociation during Drosophila wing eversion. During eversion, peripodial epithelial cells lose apico-basal polarity and adherens junctions, and become migratory and invasive - a process similar to an epithelial-mesenchymal transition. Loss of netrinA inhibits the breakdown of cell-cell junctions, leading to eversion failure. In contrast, the Netrin receptor Frazzled blocks eversion when overexpressed, whereas frazzled RNAi accelerates eversion in vitro. In peripodial cells Frazzled is endocytosed, and undergoes NetA-dependent degradation, which is required for eversion. Finally, evidence is provided that Frazzled acts through the ERM-family protein Moesin to inhibit eversion. This mechanism may also help explain the role of Netrin and DCC in cancer metastasis.

Friday, December 6th

Choi, S. H., Estaras, C., Moresco, J. J., Yates, J. R. and Jones, K. A. (2013). α-Catenin interacts with APC to regulate beta-catenin proteolysis and transcriptional repression of Wnt target genes. Genes Dev 27: 2473-2488. PubMed ID: 24240237
Summary: Mutation of the adenomatous polyposis coli (APC) tumor suppressor (see Drosophila Apc-like) stabilizes β-catenin (see Drosophila Armadillo) and aberrantly reactivates Wnt/β-catenin target genes in colon cancer. APC mutants in cancer frequently lack the conserved catenin inhibitory domain (CID), which is essential for β-catenin proteolysis. This study shows that the APC CID interacts with α-catenin (see Drosophila α-Catenin), a Hippo signaling regulator and heterodimeric partner of β-catenin at cell:cell adherens junctions. Importantly, α-catenin promotes β-catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, β-catenin ubiquitylation requires binding to α-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that α-catenin binds with β-catenin to LEF-1/TCF (see Drosophila Pangolin) DNA-binding proteins in Wnt3a signaling cells and recruits APC in a complex with the CtBP:CoREST:LSD1 histone H3K4 demethylase (see Drosophila CtBP) to regulate transcription and β-catenin occupancy at Wnt target genes. Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts binding to APC but not β-catenin and prevents repression of Wnt target genes in transformed cells. Chromatin immunoprecipitation studies further show that α-catenin and APC are recruited with β-catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of α-catenin in hESCs prevents the switch-off of Wnt/β-catenin transcription and promotes endodermal differentiation. These findings indicate a role for α-catenin in the APC destruction complex and at Wnt target genes.

Thomae, A. W., Schade, G. O., Padeken, J., Borath, M., Vetter, I., Kremmer, E., Heun, P. and Imhof, A. (2013). A pair of centromeric proteins mediates reproductive isolation in Drosophila species. Dev Cell 27: 412-424. PubMed ID: 24239514
Summary: Speciation involves the reproductive isolation of natural populations due to the sterility or lethality of their hybrids. However, the molecular basis of hybrid lethality and the evolutionary driving forces that provoke it remain largely elusive. The Hybrid male rescue (Hmr) and the Lethal hybrid rescue (Lhr) genes serve as a model to study speciation in Drosophilids because their interaction causes lethality in male hybrid offspring. This study shows that HMR and LHR form a centromeric complex necessary for proper chromosome segregation. The Hmr expression level is substantially higher in Drosophila melanogaster, whereas Lhr expression levels are increased in Drosophila simulans. The resulting elevated amount of HMR/LHR complex in hybrids results in an extensive mislocalization of the complex, an interference with the regulation of transposable elements, and an impairment of cell proliferation. These findings provide evidence for a major role of centromere divergence in the generation of biodiversity.

Kronforst, M. R., Hansen, M. E., Crawford, N. G., Gallant, J. R., Zhang, W., Kulathinal, R. J., Kapan, D. D. and Mullen, S. P. (2013). Hybridization reveals the evolving genomic architecture of speciation. Cell Rep 5: 666-677. PubMed ID: 24183670
Summary: The rate at which genomes diverge during speciation is unknown, as are the physical dynamics of the process. This study compares full genome sequences of 32 butterflies, representing five species from a hybridizing Heliconius butterfly community, to examine genome-wide patterns of introgression and infer how divergence evolves during the speciation process. These analyses reveal that initial divergence is restricted to a small fraction of the genome, largely clustered around known wing-patterning genes. Over time, divergence evolves rapidly, due primarily to the origin of new divergent regions. Furthermore, divergent genomic regions display signatures of both selection and adaptive introgression, demonstrating the link between microevolutionary processes acting within species and the origin of species across macroevolutionary timescales. These results provide a uniquely comprehensive portrait of the evolving species boundary due to the role that hybridization plays in reducing the background accumulation of divergence at neutral sites.

Thursday, December 5th

Parkinson, W., Dear, M. L., Rushton, E. and Broadie, K. (2013). N-glycosylation requirements in neuromuscular synaptogenesis. Development. PubMed ID: 24227656
Summary: Neural development requires N-glycosylation regulation of intercellular signaling, but the requirements in synaptogenesis have not been well tested. All complex and hybrid N-glycosylation requires MGAT1 (UDP-GlcNAc:alpha-3-D-mannoside-beta1,2-N-acetylglucosaminyl-transferase I) function, and Mgat1 nulls are the most compromised N-glycosylation condition that survive long enough to permit synaptogenesis studies. At the Drosophila neuromuscular junction (NMJ), Mgat1 mutants display selective loss of lectin-defined carbohydrates in the extracellular synaptomatrix, and an accompanying accumulation of the secreted endogenous Mind the gap (MTG) lectin, a key synaptogenesis regulator. Null Mgat1 mutants exhibit strongly overelaborated synaptic structural development, consistent with inhibitory roles for complex/hybrid N-glycans in morphological synaptogenesis, and strengthened functional synapse differentiation, consistent with synaptogenic MTG functions. Synapse molecular composition is surprisingly selectively altered, with decreases in presynaptic active zone Bruchpilot (BRP) and postsynaptic Glutamate receptor subtype B (GLURIIB), but no detectable change was seen in a wide range of other synaptic components. Synaptogenesis is driven by bidirectional trans-synaptic signals that traverse the glycan-rich synaptomatrix, and Mgat1 mutation disrupts both anterograde and retrograde signals, consistent with MTG regulation of trans-synaptic signaling. Downstream of intercellular signaling, pre- and postsynaptic scaffolds are recruited to drive synaptogenesis, and Mgat1 mutants exhibit loss of both classic Discs large 1 (DLG1) and newly defined Lethal (2) giant larvae [L(2)GL] scaffolds. It is concluded that MGAT1-dependent N-glycosylation shapes the synaptomatrix carbohydrate environment and endogenous lectin localization within this domain, to modulate retention of trans-synaptic signaling ligands driving synaptic scaffold recruitment during synaptogenesis.

Moore, R., Theveneau, E., Pozzi, S., Alexandre, P., Richardson, J., Merks, A., Parsons, M., Kashef, J., Linker, C. and Mayor, R. (2013). Par3 controls neural crest migration by promoting microtubule catastrophe during contact inhibition of locomotion. Development 140: 4763-4775. PubMed ID: 24173803
Summary: There is growing evidence that contact inhibition of locomotion (CIL) is essential for morphogenesis and its failure is thought to be responsible for cancer invasion; however, the molecular bases of this phenomenon are poorly understood. This study investigated the role of the polarity protein Par3 (see Drosophila Bazooka) in CIL during migration of the neural crest, a highly migratory mesenchymal cell type. In epithelial cells, Par3 is localised to the cell-cell adhesion complex and is important in the definition of apicobasal polarity, but the localisation and function of Par3 in mesenchymal cells are not well characterised. In Xenopus and zebrafish it was shown that Par3 is localised to the cell-cell contact in neural crest cells and is essential for CIL. The dynamics of microtubules are different in different parts of the cell, with an increase in microtubule catastrophe at the collision site during CIL. Par3 loss-of-function affects neural crest migration by reducing microtubule catastrophe at the site of cell-cell contact and abrogating CIL. Furthermore, Par3 promotes microtubule catastrophe by inhibiting the Rac-GEF Trio (see Drosophila Trio), as double inhibition of Par3 and Trio restores microtubule catastrophe at the cell contact and rescues CIL and neural crest migration. These results demonstrate a novel role of Par3 during neural crest migration, which is likely to be conserved in other processes that involve CIL such as cancer invasion or cell dispersion.

Ferrari, F., Plachetka, A., Alekseyenko, A. A., Jung, Y. L., Ozsolak, F., Kharchenko, P. V., Park, P. J. and Kuroda, M. I. (2013). 'Jump start and gain' model for dosage compensation in Drosophila based on direct sequencing of nascent transcripts. Cell Rep 5: 629-636. PubMed ID: 24183666
Summary: Dosage compensation in Drosophila is mediated by the MSL complex, which increases male X-linked gene expression approximately 2-fold. The MSL complex preferentially binds the bodies of active genes on the male X, depositing H4K16ac with a 3' bias. Two models have been proposed for the influence of the MSL complex on transcription: one based on promoter recruitment of RNA polymerase II (Pol II), and a second featuring enhanced transcriptional elongation. This study utilized nascent RNA sequencing to document dosage compensation during transcriptional elongation. X and autosomes from published data on paused and elongating polymerase were compared in order to assess the role of Pol II recruitment. The results support a model for differentially regulated elongation, starting with release from 5' pausing and increasing through X-linked gene bodies. The results highlight facilitated transcriptional elongation as a key mechanism for the coordinated regulation of a diverse set of genes.

Wednesday, December 4th

McKay, D. J. and Lieb, J. D. (2013). A common set of DNA regulatory elements shapes Drosophila appendages. Dev Cell 27: 306-318. PubMed ID: 24229644
Summary: Animals have body parts made of similar cell types located at different axial positions, such as limbs. The identity and distinct morphology of each structure is often specified by the activity of different 'master regulator' transcription factors. Although similarities in gene expression have been observed between body parts made of similar cell types, how regulatory information in the genome is differentially utilized to create morphologically diverse structures in development is not known. This study used formaldehyde-assisted isolation of regulatory elements (FAIRE), which identifies nucleosome-depleted or 'open' chromatin, followed by high-throughput sequencing (FAIREseq), to show that among the Drosophila appendages, the same DNA regulatory modules are accessible throughout the genome at a given stage of development, except at the loci encoding the master regulators themselves. In addition, open chromatin profiles change over developmental time, and these changes are coordinated between different appendages. It is proposed that master regulators create morphologically distinct structures by differentially influencing the function of the same set of DNA regulatory modules.

Bouchard-Cannon, P., Mendoza-Viveros, L., Yuen, A., Kaern, M. and Cheng, H. Y. (2013). The Circadian Molecular Clock Regulates Adult Hippocampal Neurogenesis by Controlling the Timing of Cell-Cycle Entry and Exit. Cell Rep. PubMed ID: 24268780
Summary: The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. This study shows that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 (see Drosophila Period and Cycle) are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. Mathematical model simulations were used to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex (see Drosophila cyclin D). These findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

Lyu, J., Kim, H. R., Yamamoto, V., Choi, S. H., Wei, Z., Joo, C. K. and Lu, W. (2013). Protein phosphatase 4 and smek complex negatively regulate par3 and promote neuronal differentiation of neural stem/progenitor cells. Cell Rep 5: 593-600. PubMed ID: 24209749
Summary: Neural progenitor cells (NPCs) are multipotent cells that can self-renew and differentiate into neurons and glial cells. However, mechanisms that control their fate decisions are poorly understood. This study shows that Smek1, a regulatory subunit of the serine/threonine protein phosphatase PP4, promotes neuronal differentiation and suppresses the proliferative capacity of NPCs. The cell polarity protein Par3 (see Drosophila Bazooka), a negative regulator of neuronal differentiation, is identified as a Smek1 substrate, and it was demonstrated that Smek1 suppresses Smek1 activity. Smek1, which is predominantly nuclear in NPCs, was also shown to be excluded from the nucleus during mitosis, allowing it to interact with cortical/cytoplasmic Par3 and mediate its dephosphorylation by the catalytic subunit PP4c. These results identify the PP4/Smek1 complex as a key regulator of neurogenesis.

Tuesday, December 3rd

Antinucci, P., Nikolaou, N., Meyer, M. P. and Hindges, R. (2013). Teneurin-3 specifies morphological and functional connectivity of retinal ganglion cells in the vertebrate visual system. Cell Rep 5: 582-592. PubMed ID: 24183672
Summary: A striking feature of the CNS is the precise wiring of its neuronal connections. During vertebrate visual system development, different subtypes of retinal ganglion cells (RGCs) form specific connections with their corresponding synaptic partners. However, the underlying molecular mechanisms remain to be fully elucidated. This study reports that the cell-adhesive transmembrane protein Teneurin-3 (Tenm3; see Drosophila Tenascin major) is required by zebrafish RGCs for acquisition of their correct morphological and functional connectivity in vivo. Teneurin-3 is expressed by RGCs and their presynaptic amacrine and postsynaptic tectal cell targets. Knockdown of Teneurin-3 leads to RGC dendrite stratification defects within the inner plexiform layer, as well as mistargeting of dendritic processes into outer portions of the retina. Moreover, a subset of RGC axons exhibits tectal laminar arborization errors. Finally, functional analysis of RGCs targeting the tectum reveals a selective deficit in the development of orientation selectivity after Teneurin-3 knockdown. These results suggest that Teneurin-3 plays an instructive role in the functional wiring of the vertebrate visual system.

Wu, C. L., Shih, M. F., Lee, P. T. and Chiang, A. S. (2013). An Octopamine-Mushroom Body Circuit Modulates the Formation of Anesthesia-Resistant Memory in Drosophila. Curr Biol. PubMed ID: 24239122
Summary: Drosophila olfactory aversive conditioning produces two components of intermediate-term memory: anesthesia-sensitive memory (ASM) and anesthesia-resistant memory (ARM). Recently, the anterior paired lateral (APL) neuron innervating the whole mushroom body (MB) has been shown to modulate ASM via gap-junctional communication in olfactory conditioning. Octopamine (OA), an invertebrate analog of norepinephrine, is involved in appetitive conditioning, but its role in aversive memory remains uncertain. This study shows that chemical neurotransmission from the anterior paired lateral (APL) neuron, after conditioning but before testing, is necessary for aversive ARM formation. The APL neurons are tyramine, Tβh, and OA immunopositive. An adult-stage-specific RNAi knockdown of Tβh in the APL neurons or Octβ2R OA receptors in the MB α'β' Kenyon cells (KCs) impaired ARM. Importantly, an additive ARM deficit occurred when Tβh knockdown in the APL neurons was in the radish mutant flies or in the wild-type flies with inhibited serotonin synthesis. It is concluded that OA released from the APL neurons acts on α'β' KCs via Octβ2R receptor to modulate Drosophila ARM formation. Additive effects suggest that two parallel ARM pathways, serotoninergic DPM-αβ KCs and octopaminergic APL-α'β' KCs, exist in the MB.

Riemensperger, T., Issa, A. R., Pech, U., Coulom, H., Nguyen, M. V., Cassar, M., Jacquet, M., Fiala, A. and Birman, S. (2013). A Single Dopamine Pathway Underlies Progressive Locomotor Deficits in a Drosophila Model of Parkinson Disease. Cell Rep. PubMed ID: 24239353
Summary: Expression of the human Parkinson-disease-associated protein alpha-synuclein in all Drosophila neurons induces progressive locomotor deficits. This study identify a group of 15 dopaminergic neurons per hemisphere in the anterior medial region of the brain whose disruption correlates with climbing impairments in this model. These neurons selectively innervate the horizontal β and β' lobes of the mushroom bodies, and their connections to the Kenyon cells are markedly reduced when they express alpha-synuclein. Using selective mushroom body drivers, it was shown that blocking or overstimulating neuronal activity in the β' lobe, but not the β or γ lobes, significantly inhibits negative geotaxis behavior. This suggests that modulation of the mushroom body β' lobes by this dopaminergic pathway is specifically required for an efficient control of startle-induced locomotion in flies.

Monday, December 2nd

Boucard, A. A., Maxeiner, S. and Sudhof, T. C. (2013). Latrophilins Function as Heterophilic Cell-Adhesion Molecules by Binding to Teneurins: Regulation by Alternative Splicing. J Biol Chem. PubMed ID: 24273166
Summary: Latrophilin-1, -2, and -3 (see Drosophila Cirl) are adhesion-type G protein-coupled receptors (GPCRs) that are auxiliary alpha-latrotoxin receptors, suggesting that they may have a synaptic function. Using pulldowns, teneurins, this study identifies type-II transmembrane proteins that are also candidate synaptic cell-adhesion molecules, as interactors for the lectin-like domain of latrophilins. Teneurin (see the Drosophila Teneurin Tenascin major:) bind to latrophilins with nanomolar affinity and this binding mediates cell-adhesion, consistent with a role of teneurin-binding to latrophilins in trans-synaptic interactions. Addition to cultured neurons of soluble, teneurin-binding fragments of latrophilin-1 decreased synapse density, suggesting that latrophilin-binding to teneurin may directly or indirectly influence synapse formation and/or maintenance. These observations are potentially intriguing in view of the proposed role for Drosophila teneurins in determining synapse specificity. However, teneurins in Drosophila were shown to act as homophilic cell-adhesion molecules, whereas the current findings suggest a heterophilic interaction mechanism. Thus, tests were performed to see whether mammalian teneurins also are homophilic cell-adhesion molecules, in addition to binding to latrophilins and FLRT3 as heterophilic cell-adhesion molecules. Strikingly, this study found that although teneurins bind to each other in solution, homophilic teneurin-teneurin binding is unable to support stable cell-adhesion, different from heterophilic teneurin-latrophilin binding. Thus, mammalian teneurins act as heterophilic cell-adhesion molecules that may be involved in trans-neuronal interaction processes such as synapse formation or maintenance.

Shyh-Chang, N., Zhu, H., Yvanka de Soysa, T., Shinoda, G., Seligson, M. T., Tsanov, K. M., Nguyen, L., Asara, J. M., Cantley, L. C. and Daley, G. Q. (2013). Lin28 enhances tissue repair by reprogramming cellular metabolism. Cell 155: 778-792
Summary: Regeneration capacity declines with age, but why juvenile organisms show enhanced tissue repair remains unexplained. Lin28a (see Drosophila Lin-28), a highly conserved RNA-binding protein expressed during embryogenesis, plays roles in development, pluripotency, and metabolism. To determine whether Lin28a might influence tissue repair in adults, the reactivation of Lin28a expression was engineered in several models of tissue injury. Lin28a reactivation improved hair regrowth by promoting anagen in hair follicles and accelerated regrowth of cartilage, bone, and mesenchyme after ear and digit injuries. Lin28a inhibits let-7 (see Drosophila let-7) microRNA biogenesis; however, let-7 repression was necessary but insufficient to enhance repair. Lin28a bound to and enhanced the translation of mRNAs for several metabolic enzymes, thereby increasing glycolysis and oxidative phosphorylation (OxPhos). Lin28a-mediated enhancement of tissue repair was negated by OxPhos inhibition, whereas a pharmacologically induced increase in OxPhos enhanced repair. Thus, Lin28a enhances tissue repair in some adult tissues by reprogramming cellular bioenergetics.

Chillakuri, C. R., Sheppard, D., Ilagan, M. X., Holt, L. R., Abbott, F., Liang, S., Kopan, R., Handford, P. A. and Lea, S. M. (2013). Structural Analysis Uncovers Lipid-Binding Properties of Notch Ligands. Cell Rep. 5(4): 861-7
Summary: The Notch pathway is a core cell-cell signaling system in metazoan organisms with key roles in cell-fate determination, stem cell maintenance, immune system activation, and angiogenesis. Signals are initiated by extracellular interactions of the Notch receptor with Delta/Serrate/Lag-2 (DSL) ligands, whose structure is highly conserved throughout evolution. To date, no structure or activity has been associated with the extreme N termini of the ligands, even though numerous mutations in this region of Jagged-1 ligand lead to human disease. Here, this study demonstrates that the N terminus of human Jagged-1 is a C2 phospholipid recognition domain that binds phospholipid bilayers in a calcium-dependent fashion. Furthermore, this activity is shared by a member of the other class of Notch ligands, human Delta-like-1 (Drosophila homolog: Delta), and the evolutionary distant Drosophila Serrate. Targeted mutagenesis of Jagged-1 C2 domain residues implicated in calcium-dependent phospholipid binding leaves Notch interactions intact but can reduce Notch activation. These results reveal an important and previously unsuspected role for phospholipid recognition in control of this key signaling system.

Sunday, December 1st

Shim, J., Mukherjee, T., Mondal, B. C., Liu, T., Young, G. C., Wijewarnasuriya, D. P. and Banerjee, U. (2013). Olfactory control of blood progenitor maintenance. Cell 155: 1141-1153
Summary: Drosophila hematopoietic progenitor maintenance involves both near neighbor and systemic interactions. This study shows that olfactory receptor neurons (ORNs) function upstream of a small set of neurosecretory cells that express GABA. Upon olfactory stimulation, GABA from these neurosecretory cells is secreted into the circulating hemolymph and binds to metabotropic GABAB receptors expressed on blood progenitors within the hematopoietic organ, the lymph gland. The resulting GABA signal causes high cytosolic Ca2+, which is necessary and sufficient for progenitor maintenance. Thus, the activation of an odorant receptor is essential for blood progenitor maintenance, and consequently, larvae raised on minimal odor environments fail to sustain a pool of hematopoietic progenitors. This study links sensory perception and the effects of its deprivation on the integrity of the hematopoietic and innate immune systems in Drosophila.

Miura, S. K., Martins, A., Zhang, K. X., Graveley, B. R. and Zipursky, S. L. (2013). Probabilistic Splicing of Dscam1 Establishes Identity at the Level of Single Neurons. Cell 155: 1166-1177
Summary: The Drosophila Dscam1 gene encodes a vast number of cell recognition molecules through alternative splicing. These exhibit isoform-specific homophilic binding and regulate self-avoidance, the tendency of neurites from the same cell to repel one another. Genetic experiments indicate that different cells must express different isoforms. How this is achieved is unknown, as expression of alternative exons in vivo has not been shown. This study modified the endogenous Dscam1 locus to generate splicing reporters for all variants of exon 4. Splicing was shown not to occur in a cell-type-specific fashion, that cells sharing the same anatomical location in different individuals express different exon 4 variants, and that the splicing pattern in a given neuron can change over time. It is concluded that splicing is probabilistic. This is compatible with a widespread role in neural circuit assembly through self-avoidance and is incompatible with models in which specific isoforms of Dscam1 mediate homophilic recognition between processes of different cells.

Link, N., Kurtz, P., O'Neal, M., Garcia-Hughes, G. and Abrams, J. M. (2013). A p53 enhancer region regulates target genes through chromatin conformations in cis and in trans. Genes Dev 27: 2433-2438. PubMed ID: 24240233
Summary: How a p53 enhancer transmits regulatory information was examined in vivo. Using genetic ablation together with digital chromosome conformation capture and fluorescent in situ hybridization, this study found that a Drosophila p53 enhancer region (referred to as the p53 response element [p53RE]) physically contacts targets in cis and across the centromere to control stress-responsive transcription at these sites. Furthermore, when placed at ectopic genomic positions, fragments spanning this element re-established chromatin contacts and partially restored target gene regulation to mutants lacking the native p53RE. Therefore, a defined p53 enhancer region is sufficient for long-range chromatin interactions that enable multigenic regulation.

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