Deshpande, G., Zhou, K., Wan, J. Y., Friedrich, J., Jourjine, N., Smith, D. and Schedl, P. (2013). The hedgehog Pathway Gene shifted Functions together with the hmgcr-Dependent Isoprenoid Biosynthetic Pathway to Orchestrate Germ Cell Migration. PLoS Genet 9: e1003720. PubMed ID: 24068944
The Drosophila embryonic gonad is assembled from two distinct cell types, the Primordial Germ Cells (PGCs) and the Somatic Gonadal Precursor cells (SGPs). The PGCs form at the posterior of blastoderm stage embryos and are subsequently carried inside the embryo during gastrulation. This study has investigated the role of the hedgehog (hh) pathway gene shifted (shf) in directing PGC migration. shf encodes a secreted protein that facilitates the long distance transmission of Hh through the proteoglycan matrix after it is released from basolateral membranes of Hh expressing cells in the wing imaginal disc. shf is expressed in the gonadal mesoderm, and loss- and gain-of-function experiments demonstrate that it is required for PGC migration. Previous studies have established that the hmgcr-dependent isoprenoid biosynthetic pathway plays a pivotal role in generating the PGC attractant both by the SGPs and by other tissues when hmgcr is ectopically expressed. Production of this PGC attractant depends upon shf as well as a second hh pathway gene gγ1. Further linking the PGC attractant to Hh, evidence is presented indicating that ectopic expression of hmgcr in the nervous system promotes the release/transmission of the Hh ligand from these cells into and through the underlying mesodermal cell layer, where Hh can contact migrating PGCs. Finally, potentiation of Hh by hmgcr appears to depend upon cholesterol modification.
Gu, T. and Elgin, S. C. (2013). Maternal Depletion of Piwi, a Component of the RNAi System, Impacts Heterochromatin Formation in Drosophila. PLoS Genet 9: e1003780. PubMed ID: 24068954
A persistent question in epigenetics is how heterochromatin is targeted for assembly at specific domains, and how that chromatin state is faithfully transmitted. Stable heterochromatin is necessary to silence transposable elements (TEs) and maintain genome integrity. Using reporters subject to Position Effect Variegation (PEV), this study found that depletion of key proteins in the early embryo can lead to loss of silencing assayed at adult stages. The piRNA component Piwi is required in the early embryo for reporter silencing in non-gonadal somatic cells, but knock-down during larval stages has no impact. This implies that Piwi is involved in targeting HP1a when heterochromatin is established at the late blastoderm stage and possibly also during embryogenesis, but that the silent chromatin state created is transmitted through cell division independent of the piRNA system. In contrast, heterochromatin structural protein HP1a is required for both initial heterochromatin assembly and the following mitotic inheritance. Piwi depletion leads to decreased HP1a levels in pericentric heterochromatin, particularly in TEs. The results suggest that the major role of the piRNA system in assembly of heterochromatin in non-gonadal somatic cells occurs in the early embryo during heterochromatin formation, and further demonstrate that failure of heterochromatin formation in the early embryo impacts the phenotype of the adult.
Sunday, September 29th
Perez-Garijo, A., Fuchs, Y. and Steller, H. (2013). Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway. Elife 2: e01004. PubMed ID: 24066226
Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. This study identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. Eiger, the Drosophila tumor necrosis factor (TNF) homolog, was identified as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. During coordinated cell death of hair follicle cells in mice, TNF-alpha is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions
Mavromatakis, Y. E. and Tomlinson, A. (2013). Switching cell fates in the developing Drosophila eye. Development 140(21): 4353-61 PubMed ID: 24067351
The developing Drosophila ommatidium is characterized by two distinct waves of pattern formation. In the first wave, a precluster of five cells is formed by a complex cellular interaction mechanism. In the second wave, cells are systematically recruited to the cluster and directed to their fates by developmental cues presented by differentiating precluster cells. These developmental cues are mediated through the receptor tyrosine kinase (RTK) and Notch (N) signaling pathways and their combined activities are crucial in specifying cell type. The transcription factor Lozenge (Lz) is expressed exclusively in second wave cells. In this study Lz was ectopically supplied to precluster cells, and the various RTK/N codes that specify each of three second wave cell fates were concomitantly supplied. This protocol reproduced molecular markers of each of the second wave cell types in first wave precluster cells. Three inferences were drawn; 1) it was confirmed that Lz provides key intrinsic information to second wave cells, and this can now be combined with the RTK/N signaling to provide a cell fate specification code that entails both extrinsic and intrinsic information. 2) the reproduction of each second wave cell type in the precluster confirms the accuracy of the RTK/N signaling code, and 3) RTK/N signaling and Lz need only be presented to the cells for a short period of time in order to specify their fate.
Saturday, September 28th
Lawlor, K. T., Ly, D. C. and Dinardo, S. (2013). Drosophila Dachsous and Fat polarize actin-based protrusions over a restricted domain of the embryonic denticle field. Dev Biol. PubMed ID: 24051227
Atypical cadherins Dachsous (Ds) and Fat coordinate the establishment of planar polarity, essential for the patterning of complex tissues and organs. Using the asymmetric placement of f-actin during denticle assembly as a read-out of polarity, this study examined the requirement for Ds and Fat in establishing polarity across the denticle field. Comparing detailed phenotypic analysis with steady state protein enrichment revealed a spatially restricted requirement for the Ds-Fat system within the posterior denticle field. Ectopic Ds signaling provides evidence for a model whereby Ds acts to asymmetrically enrich Fat in a neighboring cell, in turn polarizing the cell to specify the position of the actin-based protrusions at the cell cortex.
Ong, C. T., Van Bortle, K., Ramos, E. and Corces, V. G. (2013). Poly(ADP-ribosyl)ation Regulates Insulator Function and Intrachromosomal Interactions in Drosophila. Cell. PubMed ID: 24055367
Insulators mediate inter- and intrachromosomal contacts to regulate enhancer-promoter interactions and establish chromosome domains. The mechanisms by which insulator activity can be regulated to orchestrate changes in the function and three-dimensional arrangement of the genome remain elusive. This study demonstrates that Drosophila insulator proteins are poly(ADP-ribosyl)ated and that mutation of the poly(ADP-ribose) polymerase (Parp) gene impairs their function. This modification is not essential for DNA occupancy of insulator DNA-binding proteins
dCTCF and Su(Hw). However, poly(ADP-ribosyl)ation of K566 in
CP190 promotes protein-protein interactions with other insulator proteins, association with the nuclear lamina, and insulator activity in vivo. Consistent with these findings, the nuclear clustering of CP190 complexes is disrupted in Parp mutant cells. Importantly, poly(ADP-ribosyl)ation facilitates intrachromosomal interactions between insulator sites measured by 4C. These data suggest that the role of insulators in organizing the three-dimensional architecture of the genome may be modulated by poly(ADP-ribosyl)ation.
Friday, September 27th
Abramsson, A., Kettunen, P., Banote, R. K., Lott, E., Li, M., Arner, A. and Zetterberg, H. (2013). The zebrafish amyloid precursor protein-b is required for motor neuron guidance and synapse formation. Dev Biol 381: 377-388. PubMed ID: 23850871
The amyloid precursor protein (APP: see Drosophila β amyloid protein precursor-like) is a transmembrane protein mostly recognized for its association with Alzheimer's disease. The physiological function of APP is still not completely understood much because of the redundancy between genes in the APP family. This study used zebrafish to study the physiological function of the zebrafish APP homologue, appb, during development. appb was shown to be expressed in post-mitotic neurons in the spinal cord. Knockdown of appb by 50-60% results in a behavioral phenotype with increased spontaneous coiling and prolonged touch-induced activity. The spinal cord motor neurons in these embryos show defective formation and axonal outgrowth patterning. Reduction in Appb also results in patterning defects and changed density of pre- and post-synapses in the neuromuscular junctions. Together, these data show that development of functional locomotion in zebrafish depends on a critical role of Appb in the patterning of motor neurons and neuromuscular junctions.
Dunipace, L., Saunders, A., Ashe, H. L. and Stathopoulos, A. (2013). Autoregulatory Feedback Controls Sequential Action of cis-Regulatory Modules at the brinker Locus. Dev Cell 26: 536-543. PubMed ID: 24044892
cis-regulatory modules (CRMs) act sequentially to regulate temporal expression of genes, but how the switch from one to the next is accomplished is not well understood. To provide insight, this study investigated the cis-regulatory system controlling brinker (brk) expression in the Drosophila embryo. Two distally located CRMs support expression at different times, while a promoter-proximal element (PPE) is required to support their action. In the absence of Brk protein itself or upon mutagenesis of Brk binding sites within the PPE, the late-acting CRM, specifically, is delayed. This block to late-acting CRM function appears to be removed when the early-acting CRM is also deleted. These results demonstrate that autoregulatory feedback is necessary for the early-acting CRM to disengage from the promoter so that the late-acting CRM may act. Autoregulation may be a commonly used mechanism to control sequential CRM action necessary for dynamic gene expression throughout the course of development.
Thursday, September 26th
Nolte, C., Jinks, T., Wang, X., Pastor, M. T. and Krumlauf, R. (2013). Shadow Enhancers Flanking the HoxB Cluster Direct Dynamic Hox Expression in Early Heart and Endoderm Development. Dev Biol. PubMed ID: 24055171
Several novel enhancers flanking the HoxB complex (see Drosophila Antennapedia and Bithorax complexes) have been identified that can work over a long range to mediate dynamic reporter expression in the endoderm and embryonic heart during development. These enhancers respond to exogenously added retinoic acid, and two retinoic acid response elements (RAREs) have been identified within these control modules that play a role in potentiating their regulatory activity. These control modules, spread throughout the flanking intergenic region, have regulatory activities that overlap with other local enhancers. This suggests that they function as shadow enhancers to modulate the expression of genes from the HoxB complex during cardiac development. Regulatory analysis of the HoxA complex reveals that it also has enhancers in the 3′ flanking region which contain RAREs and have the potential to modulate expression in endoderm and heart tissues. A common regulatory mechanism is suggested whereby the conserved control modules act over a long range on multiple Hox genes to generate nested patterns of HoxA and HoxB expression during cardiogenesis.
Zirin, J., Cheng, D., Dhanyasi, N., Cho, J., Dura, J. M., Vijayraghavan, K. and Perrimon, N. (2013). Ecdysone signaling at metamorphosis triggers apoptosis of Drosophila abdominal muscles. Dev Biol. PubMed ID: 24051228
One of the most dramatic examples of programmed cell death occurs during Drosophila metamorphosis, when most of the larval tissues are destroyed in a process termed histolysis. Much of our understanding of this process comes from analyses of salivary gland and midgut cell death. In contrast, relatively little is known about the degradation of the larval musculature. This study analyzed the programmed destruction of the abdominal dorsal exterior oblique muscle (DEOM) which occurs during the first 24h of metamorphosis. Ecdysone signaling through Ecdysone receptor isoform B1 is required cell autonomously for the muscle death. Furthermore, the orphan nuclear receptor FTZ-F1, opposed by another nuclear receptor, HR39, plays a critical role in the timing of DEOM histolysis. Unlike the histolysis of salivary gland and midgut, abdominal muscle death occurs by apoptosis, and does not require autophagy. Thus, there is no set rule as to the role of autophagy and apoptosis during Drosophila histolysis.
Wednesday, September 25th
Chonko, K. T., Jahan, I., Stone, J., Wright, M. C., Fujiyama, T., Hoshino, M., Fritzsch, B. and Maricich, S. M. (2013). Atoh1 directs hair cell differentiation and survival in the late embryonic mouse inner ear. Dev Biol 381: 401-410. PubMed ID: 23796904
Summary: Atoh1 (Drosophila homolog: Atonal) function is required for the earliest stages of inner ear hair cell development, which begins during the second week of gestation. Atoh1 expression in developing hair cells continues until early postnatal ages, but the function of this late expression is unknown. To test the role of continued Atoh1 expression in hair cell maturation the gene was conditionally deleted in the inner ear at various embryonic and postnatal ages. In the organ of Corti, deletion of Atoh1 at E15.5 led to the death of all hair cells. In contrast, deletion at E16.5 caused death only in apical regions, but abnormalities of stereocilia formation were present throughout the cochlea. In the utricle, deletion at E14.5 or E16.5 did not cause cell death but led to decreased expression of myosin VIIa (Drosophila homolog: crinkled) and failure of stereocilia formation. Furthermore, maintenance of expression of Barhl1 and Gfi1, two transcription factors implicated in cochlear hair cell survival, depends upon continued Atoh1 expression. These data reveal novel late roles for Atoh1 that are separable from its initial role in hair cell development.
Humphreys, G. B., Jud, M. C., Monroe, K. M., Kimball, S. S., Higley, M., Shipley, D., Vrablik, M. C., Bates, K. L. and Letsou, A. (2013). Mummy, A UDP-N-acetylglucosamine pyrophosphorylase, modulates DPP signaling in the embryonic epidermis of Drosophila. Dev Biol 381: 434-445. PubMed ID: 23796903
Summary: The evolutionarily conserved JNK/AP-1 (Jun N-terminal kinase/activator protein 1) and BMP (Bone Morphogenetic Protein) signaling cascades are deployed hierarchically to regulate dorsal closure in Drosophila. In this developmental context, the JNK/AP-1 signaling cascade transcriptionally activates BMP signaling in leading edge epidermal cells. This study shows that the mummy (mmy) gene product, which is required for dorsal closure, functions as a BMP signaling antagonist. The mmy gene product is a new type of epidermal BMP regulator - one which transforms a BMP ligand (see Drosophila Dpp) from a long- to a short-range signal. mmy codes for the single UDP-N-acetylglucosamine pyrophosphorylase in Drosophila, and its requirement for attenuating epidermal BMP signaling during dorsal closure points to a new role for glycosylation in defining a highly restricted BMP activity field in the fly. These findings add a new dimension to understanding of mechanisms modulating the BMP signaling gradient.
Tuesday, September 24
Togel, M., Meyer, H., Lehmacher, C., Heinisch, J. J., Pass, G. and Paululat, A. (2013). The bHLH transcription factor hand is required for proper wing heart formation in Drosophila. Dev Biol 381: 446-459. PubMed ID: 23747982
Summary: The Hand basic helix-loop-helix transcription factors play an important role in the specification and patterning of various tissues in vertebrates and invertebrates. This study has investigated the function of Hand in the development of the Drosophila wing hearts which consist of somatic muscle cells as well as a mesodermally derived epithelium. Hand is essential in both tissues for proper organ formation. Loss of Hand leads to a reduced number of cells in the mature organ and loss of wing heart functionality. In wing heart muscles Hand is required for the correct positioning of attachment sites, the parallel alignment of muscle cells, and the proper orientation of myofibrils. At the protein level, alpha-Spectrin and Dystroglycan are misdistributed suggesting a defect in the costameric network. Hand is also required for proper differentiation of the wing heart epithelium. Additionally, the handC-GFP reporter line is not active in the mutant suggesting an autoregulatory role of Hand in wing hearts. Finally, in a candidate-based RNAi mediated knock-down approach, Daughterless and Nautilus were identified as potential dimerization partners of Hand in wing hearts.
Yonehara, K., Farrow, K., Ghanem, A., Hillier, D., Balint, K., Teixeira, M., Juttner, J., Noda, M., Neve, R. L., Conzelmann, K. K. and Roska, B. (2013). The first stage of cardinal direction selectivity is localized to the dendrites of retinal ganglion cells. Neuron 79: 1078-1085. PubMed ID: 23973208
Inferring the direction of image motion is a fundamental component of visual computation and essential for visually guided behavior. In the mammalian retina, the direction of image motion is computed in four cardinal directions, but it is not known at which circuit location along the flow of visual information the cardinal direction selectivity first appears. This study recorded the concerted activity of the neuronal circuit elements of single direction-selective (DS) retinal ganglion cells at subcellular resolution by combining GCaMP3-functionalized transsynaptic viral tracing and two-photon imaging. While the visually evoked activity of the dendritic segments of the DS cells were direction selective, direction-selective activity was absent in the axon terminals of bipolar cells. Furthermore, the glutamate input to DS cells, recorded using a genetically encoded glutamate sensor, also lacked direction selectivity. Therefore, the first stage in which extraction of a cardinal motion direction occurs is the dendrites of DS cells.
Monday, September 23
Dimidschstein, J., Passante, L., Dufour, A., van den Ameele, J., Tiberi, L., Hrechdakian, T., Adams, R., Klein, R., Lie, D. C., Jossin, Y. and Vanderhaeghen, P. (2013).. Ephrin-b1 controls the columnar distribution of cortical pyramidal neurons by restricting their tangential migration. Neuron 79: 1123-1135. PubMed ID: 24050402
Neurons of the cerebral cortex are organized in layers and columns. Unlike laminar patterning, the mechanisms underlying columnar organization remain largely unexplored. This study shows that ephrin-B1 (see Drosophila Ephrin) plays a key role in this process through the control of nonradial steps of migration of pyramidal neurons. In vivo gain of function of ephrin-B1 results in a reduction of tangential motility of pyramidal neurons, leading to abnormal neuronal clustering. Conversely, following genetic disruption of ephrin-B1, cortical neurons display a wider lateral dispersion, resulting in enlarged ontogenic columns. Dynamic analyses revealed that ephrin-B1 controls the lateral spread of pyramidal neurons by limiting neurite extension and tangential migration during the multipolar phase. Furthermore, P-Rex1, a guanine-exchange factor for Rac3, was identified as a downstream ephrin-B1 effector required to control migration during the multipolar phase. These results demonstrate that ephrin-B1 inhibits nonradial migration of pyramidal neurons, thereby controlling the pattern of cortical columns.
Niessen, M. T., Scott, J., Zielinski, J. G., Vorhagen, S., Sotiropoulou, P. A., Blanpain, C., Leitges, M. and Niessen, C. M. (2013). aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation. J Cell Biol 202: 887-900. PubMed ID: 24019538
The atypical protein kinase C (aPKC; see Drosophila polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. This study shows that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbs tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ alters the fate of lower bulge/hair germ stem cells. This ultimately leads to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produces more asymmetric divisions in different compartments, including the bulge. Thus, aPKClambda is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.
Sunday, September 22nd
Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T. and Shatz, C. J. (2013). Human LilrB2 is a β-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 341: 1399-1404. PubMed ID: 24052308
Soluble β-amyloid (Aβ) oligomers (see Drosophila Appl) impair synaptic plasticity and cause synaptic loss associated with Alzheimer's disease (AD). Murine PirB (paired immunoglobulin-like receptor B) and its human ortholog LilrB2 (leukocyte immunoglobulin-like receptor B2), present in human brain and acting as known receptors for major histocompatibility complex class I antigen, are receptors for Aβ oligomers, with nanomolar affinity. The first two extracellular immunoglobulin (Ig) domains of PirB and LilrB2 mediate this interaction, leading to enhanced cofilin signaling, also seen in human AD brains. In mice, the deleterious effect of Aβ oligomers on hippocampal long-term potentiation require PirB, and in a transgenic model of AD, PirB not only contribute to memory deficits present in adult mice, but also mediate loss of synaptic plasticity in juvenile visual cortex. These findings imply that LilrB2 contributes to human AD neuropathology and suggest therapeutic uses of blocking LilrB2 function.
Yin, F., Yu, J., Zheng, Y., Chen, Q., Zhang, N. and Pan, D. (2013). Spatial Organization of Hippo Signaling at the Plasma Membrane Mediated by the Tumor Suppressor Merlin/NF2. Cell 154: 1342-1355. PubMed ID: 24012335
Although Merlin/NF2 (see Drosophila Merlin) was discovered two decades ago as a tumor suppressor underlying Neurofibromatosis type II, its precise molecular mechanism remains poorly understood. Recent studies in Drosophila revealed a potential link between Merlin and the Hippo pathway by placing Merlin genetically upstream of the kinase Hpo/Mst. This study shows that in both Drosophila and mammals, Merlin promotes downstream Hippo signaling without activating the intrinsic kinase activity of Hpo/Mst. Instead, Merlin directly binds and recruits the effector kinase Wts/Lats (see Drosophila Warts) to the plasma membrane. Membrane recruitment, in turn, promotes Wts phosphorylation by the Hpo-Sav kinase complex. This study further shows that disruption of the actin cytoskeleton promotes Merlin-Wts interactions, which implicates Merlin in actin-mediated regulation of Hippo signaling. These findings elucidate an important molecular function of Merlin and highlight the plasma membrane as a critical subcellular compartment for Hippo signal transduction (Yin, 2013).
Saturday, September 21st
Hu, D. J., Baffet, A. D., Nayak, T., Akhmanova, A., Doye, V. and Vallee, R. B. (2013). Dynein recruitment to nuclear pores activates apical nuclear migration and mitotic entry in brain progenitor cells. Cell 154: 1300-1313. PubMed ID: 24034252
Summary: Radial glial progenitors (RGPs) are elongated epithelial cells that give rise to neurons, glia, and adult stem cells during brain development. RGP nuclei migrate basally during G1, apically using cytoplasmic dynein (see Drosophila Dynein) during G2, and undergo mitosis at the ventricular surface. This study found that two distinct G2-specific mechanisms for dynein nuclear pore recruitment are essential for apical nuclear migration. The "RanBP2-BicD2" and "Nup133-CENP-F" pathways act sequentially, with Nup133 or centromere protein F (CENP-F RNAi) arresting nuclei close to the ventricular surface in a premitotic state. Forced targeting of dynein to the nuclear envelope rescues nuclear migration and cell-cycle progression, demonstrating that apical nuclear migration is not simply correlated with cell-cycle progression from G2 to mitosis, but rather, is a required event. These results reveal that cell-cycle control of apical nuclear migration occurs by motor protein recruitment and identify a role for nucleus- and centrosome-associated forces in mitotic entry.
Tian, C., Shi, H., Xiong, S., Hu, F., Xiong, W. C. and Liu, J. (2013). The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans. Development 140: 4070-4080. PubMed ID: 24004951
The deleted in colorectal cancer (DCC) homolog neogenin (see Drosophila Frazzled), functions in both netrin- and repulsive guidance molecule (RGM)-mediated axon guidance and in bone morphogenetic protein (BMP) signaling. How neogenin functions in mediating BMP signaling is not well understood. This study shows that the sole C. elegans DCC/neogenin homolog UNC-40 positively modulates a BMP-like pathway by functioning in the signal-receiving cells at the ligand/receptor level. This function of UNC-40 is independent of its role in netrin-mediated axon guidance, but requires its association with the repulsive guidance molecule DRAG-1. This study has identified the key residues in the extracellular domain of UNC-40 that are crucial for UNC-40-DRAG-1 interaction and UNC-40 function. Surprisingly, the extracellular domain of UNC-40 is sufficient to promote BMP signaling, in clear contrast to the requirement of its intracellular domain in mediating axon guidance. Mouse neogenin lacking the intracellular domain is also capable of mediating BMP signaling. These findings reveal an unexpected mode of action for neogenin regulation of BMP signaling.
Friday, September 20th
Xu, X., Brechbiel, J. L. and Gavis, E. R. (2013). Dynein-Dependent Transport of nanos RNA in Drosophila Sensory Neurons Requires Rumpelstiltskin and the Germ Plasm Organizer Oskar. J Neurosci 33: 1479800. PubMed ID: 24027279
Summary: Intracellular mRNA localization is a conserved mechanism for spatially regulating protein production in polarized cells, such as neurons. The mRNA encoding the translational repressor Nanos (Nos) forms ribonucleoprotein (RNP) particles that are dendritically localized in Drosophila larval class IV dendritic arborization (da) neurons. In nos mutants, class IV da neurons exhibit reduced dendritic branching complexity. This study investigated the mechanism of dendritic nos mRNA localization by analyzing requirements for nos RNP particle motility in class IV da neuron dendrites. Dynein motor machinery components were shown to mediate transport of nos mRNA in proximal dendrites. Two factors, the RNA-binding protein Rumpelstiltskin and the germ plasm protein Oskar function in da neurons for formation and transport of nos RNP particles. nos was shown to regulate neuronal function, most likely independently of its dendritic localization and function in morphogenesis. These results reveal adaptability of localization factors for regulation of a target transcript in different cellular contexts.
van der Velden, Y. U., Wang, L., Querol Cano, L. and Haramis, A. P. (2013). The polycomb group protein ring1b/rnf2 is specifically required for craniofacial development. PLoS One 8: e73997. PubMed ID: 24040141
Polycomb group (PcG) genes are chromatin modifiers that mediate epigenetic silencing of target genes. Zebrafish Ring1b/Rnf2 (see Drosophila Sex combs extra), the single E3 ubiquitin ligase in the Polycomb Repressive Complex 1, critically regulates the developmental program of craniofacial cell lineages. Zebrafish ring1b mutants display a severe craniofacial phenotype, which includes an almost complete absence of all cranial cartilage, bone and musculature. This study shows that Cranial Neural Crest (CNC)-derived cartilage precursors migrate correctly into the pharyngeal arches, but fail to differentiate into chondrocytes. The results reveal a critical and specific role for Ring1b in promoting the differentiation of cranial neural crest cells into chondrocytes. The zebrafish ring1b mutant provides a molecular model for investigating mechanisms underlying craniofacial abnormalities.
Thursday September 19th
Slattery, M., Voutev, R., Ma, L., Negre, N., White, K. P. and Mann, R. S. (2013). Divergent transcriptional regulatory logic at the intersection of tissue growth and developmental patterning. PLoS Genet 9: e1003753. PubMed ID: 24039600
The Yorkie/Yap transcriptional coactivator is a well-known regulator of cellular proliferation in both invertebrates and mammals. As a coactivator, Yorkie (Yki) lacks a DNA binding domain and must partner with sequence-specific DNA binding proteins in the nucleus to regulate gene expression; in Drosophila, the developmental regulators Scalloped (Sd) and Homothorax (Hth) are two such partners. To determine the range of target genes regulated by these three transcription factors, genome-wide chromatin immunoprecipitation experiments for each factor was performed in both the wing and eye-antenna imaginal discs. Strong, tissue-specific binding patterns are observed for Sd and Hth, while Yki binding is remarkably similar across both tissues. Binding events common to the eye and wing are also present for Sd and Hth; these are associated with genes regulating cell proliferation and 'housekeeping' functions. In contrast, tissue-specific binding events for Sd and Hth significantly overlap enhancers that are active in the given tissue, are enriched in Sd and Hth DNA binding sites, respectively, and are associated with genes that are consistent with each factor's tissue-specific functions. Overall these results suggest that both Sd and Hth use distinct strategies - one shared between tissues and associated with Yki, the other tissue-specific, generally Yki-independent and associated with developmental patterning - to regulate distinct gene sets during development.
Tan, Y., Yu, D., Busto, G. U., Wilson, C. and Davis, R. L. (2013). Wnt Signaling Is Required for Long-Term Memory Formation. Cell Rep. PubMed ID: 24035392
Wnt signaling regulates synaptic plasticity and neurogenesis in the adult nervous system, suggesting a potential role in behavioral processes. This study probed the requirement for Wnt signaling during olfactory memory formation in Drosophila using an inducible RNAi approach. Interfering with Armadillo/β-catenin expression in adult mushroom body neurons specifically impaired long-term memory (LTM) without altering short-term memory. The impairment was reversible, being rescued by expression of a wild-type β-catenin transgene, and correlated with disruption of a cellular LTM trace. Inhibition of wingless, a Wnt ligand, and arrow, a Wnt coreceptor, also impaired LTM. Wingless expression in wild-type flies was transiently elevated in the brain after LTM conditioning. Thus, inhibiting three key components of the Wnt signaling pathway in adult mushroom bodies impairs LTM, indicating that this pathway mechanistically underlies this specific form of memory
Wednesday, September 18th
Zwart, M. F., Randlett, O., Evers, J. F. and Landgraf, M. (2013). Dendritic growth gated by a steroid hormone receptor underlies increases in activity in the developing Drosophila locomotor system. Proc Natl Acad Sci U S A. PubMed ID: 24043825
Summary: Motoneurons at the Drosophila neuromuscular junctions are known to enlarge their presynaptic axon terminals in size and strength, thereby compensating for reductions in muscle excitability that are associated with increases in muscle size. How motoneurons change in the central nervous system was studied during periods of animal growth. Within the central nervous system motoneurons also enlarge their postsynaptic dendritic arbors, by the net addition of branches, and these scale with overall animal size. This dendritic growth is gated on a cell-by-cell basis by a specific isoform of the steroid hormone receptor ecdysone receptor-B2. The dendritic growth is accompanied by synaptic strengthening and results in increased neuronal activity. Electrical properties of these neurons, however, are independent of ecdysone receptor-B2 regulation. It is proposed that these structural dendritic changes in the central nervous system, which regulate neuronal activity, constitute an additional part of the adaptive response of the locomotor system to increases in body and muscle size as the animal grows.
Pferdehirt, R. R. and Meyer, B. J. (2013). SUMOylation is essential for sex-specific assembly and function of the Caenorhabditis elegans dosage compensation complex on X chromosomes. Proc Natl Acad Sci U S A. PubMed ID: 24043781
Summary: The essential process of dosage compensation equalizes X-chromosome gene expression between C. elegans XO males and XX hermaphrodites through a dosage compensation complex (DCC) that is homologous to condensin. The DCC binds to both X chromosomes of hermaphrodites to repress transcription by half. This study shows that posttranslational modification by the SUMO (small ubiquitin-like modifier) conjugation pathway (see Drosophila SUMO) is essential for sex-specific assembly and function of the DCC on X. Three DCC subunits are SUMOylated, and SUMO depletion preferentially reduces their binding to X, suggesting that SUMOylation of DCC subunits is essential for robust association with X. DCC SUMOylation is triggered by the signal that initiates DCC assembly onto X. DCC subunits also participate in condensin complexes essential for chromosome segregation, but their SUMOylation occurs only in the context of the DCC. These results reinforce a newly emerging theme in which multiple proteins of a complex are collectively SUMOylated in response to a specific stimulus, leading to accelerated complex formation and enhanced function.
Tuesday, September 17th
Whitfield, Z. J., Chisholm, J., Hawley, R. S. and Orr-Weaver, T. L. (2013). A Meiosis-Specific Form of the APC/C Promotes the Oocyte-to-Embryo Transition by Decreasing Levels of the Polo Kinase Inhibitor Matrimony. PLoS Biol 11: e1001648. PubMed ID: 24019759
The Drosophila protein Cortex (Cort) is a female, meiosis-specific activator of the Anaphase Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. The Polo kinase inhibitor Matrimony (Mtrm) has been identified an interactor with Cort. Mtrm protein is reduced dramatically during the oocyte-to-embryo transition, and this downregulation does not take place in cort mutant eggs, consistent with Mtrm being a substrate of APC(Cort). Mtrm is subject to APC(Cort)-mediated proteasomal degradation and a putative APC/C recognition motif has been identified in Mtrm that when mutated partially stabilized the protein in the embryo. Furthermore, overexpression of Mtrm in the early embryo caused aberrant nuclear divisions and developmental defects, and these are enhanced by decreasing levels of active Polo. These data indicate APC(Cort) ubiquitylates Mtrm at the oocyte-to-embryo transition, thus preventing excessive inhibition of Polo kinase activity due to Mtrm's presence.
Carney, T. D., Struck, A. J. and Doe, C. Q. (2013). midlife crisis encodes a conserved zinc-finger protein required to maintain neuronal differentiation in Drosophila. Development. PubMed ID: 24026126
This study reports the identification of midlife crisis (mdlc; CG4973) as a gene required for the maintenance of neuronal differentiation and for neuroblast proliferation in Drosophila. mdlc encodes a ubiquitously expressed zinc-finger-containing protein with conserved orthologs from yeast to humans that are reported to have a role in RNA splicing. Using clonal analysis, it was demonstrated that mdlc mutant neurons initiate but fail to complete differentiation, as judged by the loss of the pro-differentiation transcription factor Prospero, followed by derepression of the neuroblast factors Deadpan, Asense and Cyclin E. Loss of Mdlc decreases pros transcript levels and results in aberrant pros splicing. Importantly, misexpression of the full-length human ortholog, RNF113A, completely rescues all CNS defects in mdlc mutants. It is concluded that Mdlc plays an essential role in maintaining neuronal differentiation, raising the possibility that RNF113A regulates neuronal differentiation in the human CNS.
Monday, September 16th
Parnas, M., Lin, A. C., Huetteroth, W. and Miesenbock, G. (2013). Odor discrimination in Drosophila: from neural population codes to behavior. Neuron 79: 932-944. PubMed ID: 24012006
Summary: Taking advantage of the well-characterized olfactory system of Drosophila, this study derive a simple quantitative relationship between patterns of odorant receptor activation, the resulting internal representations of odors, and odor discrimination. Second-order excitatory and inhibitory projection neurons (ePNs and iPNs) convey olfactory information to the lateral horn, a brain region implicated in innate odor-driven behaviors. The distance between ePN activity patterns was shown to be the main determinant of a fly's spontaneous discrimination behavior. Manipulations that silence subsets of ePNs have graded behavioral consequences, and effect sizes are predicted by changes in ePN distances. ePN distances predict only innate, not learned, behavior because the latter engages the mushroom body, which enables differentiated responses to even very similar odors. Inhibition from iPNs, which scales with olfactory stimulus strength, enhances innate discrimination of closely related odors, by imposing a high-pass filter on transmitter release from ePN terminals that increases the distance between odor representations.
Perisse, E., Yin, Y., Lin, A. C., Lin, S., Huetteroth, W. and Waddell, S. (2013). Different kenyon cell populations drive learned approach and avoidance in Drosophila. PubMed ID: Neuron 79: 945-956. PubMed ID: 24012007
In Drosophila, anatomically discrete dopamine neurons that innervate distinct zones of the mushroom body (MB) assign opposing valence to odors during olfactory learning. Subsets of MB neurons have temporally unique roles in memory processing, but valence-related organization has not been demonstrated. This study functionally subdivided the αβ neurons, revealing a value-specific role for the approximately 160 αβ core neurons. Blocking neurotransmission from αβ surface neurons revealed a requirement during retrieval of aversive and appetitive memory, whereas blocking αβ core only impaired appetitive memory. The αβ core were also required to express memory in a differential aversive paradigm demonstrating a role in relative valuation and approach behavior. Strikingly, both reinforcing dopamine neurons and efferent pathways differentially innervate αβ core and αβ surface in the MB lobes. It is proposed that conditioned approach requires pooling synaptic outputs from across the αβ ensemble but only from the αβ surface for conditioned aversion.
Sunday, September 15th
Rogers, W. A., Salomone, J. R., Tacy, D. J., Camino, E. M., Davis, K. A., Rebeiz, M. and Williams, T. M. (2013). Recurrent modification of a conserved cis-regulatory element underlies fruit fly pigmentation diversity. PLoS Genet 9: e1003740. PubMed ID: 24009528
In Drosophila melanogaster fruit flies, the Bric-a-brac (Bab) transcription factors control the development of a suite of sexually dimorphic traits on the posterior abdomen. Female-specific Bab expression is regulated by the dimorphic element, a CRE that possesses direct inputs from body plan (Abd-B) and sex-determination (Dsx) transcription factors. This study finds that the recurrent evolutionary modification of this CRE underlies both intraspecific and interspecific variation in female pigmentation in the melanogaster species group. By reconstructing the sequence and regulatory activity of the ancestral Drosophila melanogaster dimorphic element, this study demonstrates that a handful of mutations are sufficient to create independent CRE alleles with differing activities. Moreover, intraspecific and interspecific dimorphic element evolution proceeds with little to no alterations to the known body plan and sex-determination regulatory linkages. Collectively, these findings represent an example where the paths of evolution appear biased to a specific CRE, and drastic changes in function are accompanied by deep conservation of key regulatory linkages.
Liang, L., Li, Y., Potter, C. J., Yizhar, O., Deisseroth, K., Tsien, R. W. and Luo, L. (2013). GABAergic projection neurons route selective olfactory inputs to specific higher-order neurons. Neuron 79: 917-931. PubMed ID: 24012005
This study characterized an inhibitory circuit motif in the Drosophila olfactory system, parallel inhibition, which differs from feedforward or feedback inhibition. Excitatory and GABAergic inhibitory projection neurons (ePNs and iPNs) each receive input from antennal lobe glomeruli and send parallel output to the lateral horn, a higher center implicated in regulating innate olfactory behavior. Ca2+ imaging of specific lateral horn neurons as an olfactory readout revealed that iPNs selectively suppress food-related odor responses, but spare signal transmission from pheromone channels. Coapplying food odorant does not affect pheromone signal transmission, suggesting that the differential effects likely result from connection specificity of iPNs, rather than a generalized inhibitory tone. Ca2+ responses in the ePN axon terminals show no detectable suppression by iPNs, arguing against presynaptic inhibition as a primary mechanism. The parallel inhibition motif may provide specificity in inhibition to funnel specific olfactory information, such as food and pheromone, into distinct downstream circuits.
Summary: Interphase chromatin is partitioned into spatially segregated Mb-sized compartments and sub-Mb-sized topological domains. This compartmentalization is thought to facilitate the matching of genes and regulatory elements. Cohesin (see Drosophila Rad21) controls chromosome topology to enable DNA repair and chromosome segregation in cycling cells. In addition, cohesin associates with active enhancers and promoters and with CTCF (see Drosophila CTCF) to form long-range interactions important for gene regulation. This study found that architectural compartments are maintained in non-cycling mouse thymocytes after genetic depletion of cohesin. Cohesin is however required for specific long-range interactions within compartments where cohesin-regulated genes reside. Cohesin depletion diminishes interactions between cohesin-bound sites, while alternative interactions between chromatin features associated with transcriptional activation and repression became more prominent, with corresponding changes in gene expression. These findings indicate that cohesin-mediated long-range interactions facilitate discrete gene expression states within pre-existing chromosomal compartments
Atkins, M., Jiang, Y., Sansores-Garcia, L., Jusiak, B., Halder, G. and Mardon, G. (2013). Dynamic rewiring of the Drosophila retinal determination network switches its function from selector to differentiation. PLoS Genet 9: e1003731. PubMed ID: 24009524
Organ development is directed by selector gene networks. Eye development in Drosophila is driven by the highly conserved selector gene network referred to as the "retinal determination gene network." This study identified a switch in the regulation of the selector gene eyeless (ey) by the downstream retinal determination genes, that is essential for the transition from determination to differentiation. Central to the transition is a switch from positive regulation of ey transcription to negative regulation; both types of regulation require sine oculus. The results suggest a model in which the retinal determination gene network is rewired to end the growth and determination stage of eye development and trigger terminal differentiation. It is concluded that changes in the regulatory relationships among members of the retinal determination gene network are a driving force for key transitions in retinal development.
Friday, September 13th
Wu, J., Roman, A. C., Carvajal-Gonzalez, J. M. and Mlodzik, M. (2013). Wg and Wnt4 provide long-range directional input to planar cell polarity orientation in Drosophila. Nat Cell Biol 15: 1045-1055. PubMed ID: 23912125
Summary: Planar cell polarity (PCP) is cellular polarity within the plane of an epithelial tissue or organ. PCP is established through interactions of the core Frizzled (Fz)/PCP factors and, although their molecular interactions are beginning to be understood, the upstream input providing the directional bias and polarity axis remains unknown. Among core PCP genes, Fz is unique as it regulates PCP both cell-autonomously and non-autonomously, with its extracellular domain acting as a ligand for Van Gogh (Vang). This study demonstrates in Drosophila wings that Wg (Wingless) and dWnt4 provide instructive regulatory input for PCP axis determination, establishing polarity axes along their graded distribution and perpendicular to their expression domain borders. Loss-of-function studies reveal that Wg and dWnt4 act redundantly in PCP determination. They affect PCP by modulating the intercellular interaction between Fz and Vang, which is thought to be a key step in setting up initial polarity, thus providing directionality to the PCP process.
Fachinetti, D., et al. (2013). A two-step mechanism for epigenetic specification of centromere identity and function. Nat Cell Biol 15: 1056-1066. PubMed ID: 23873148
The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A (see the Drosophila homolog Centromere identifier) is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively.
Thursday, September 12th
Bergstralh, D. T., Lovegrove, H. E. and St Johnston, D.S (2013). Discs Large Links Spindle Orientation to Apical-Basal Polarity in Drosophila Epithelia Discs Large Links Spindle Orientation to Apical-Basal Polarity in Drosophila Epithelia. Curr Biol. Curr Biol. 23: 1707-1712. PubMed ID: 23891112
Summary: Mitotic spindles in epithelial cells are oriented in the plane of the epithelium so that both daughter cells remain within the monolayer. This study shows that spindle orientation requires the lateral factor Discs large (Dlg), a function that is separable from its role in epithelial polarity. In neuroblasts, Pins recruits Dlg and Mud to form an apical complex that orients spindles along the apical-basal axis. This study shows that Pins and Mud are also necessary for spindle orientation in follicle cells, as is the interaction between Dlg and Pins. Dlg localizes independently of Pins, however, suggesting that its lateral localization determines the planar orientation of the spindle in epithelial cells. Thus, different mechanisms recruit the conserved Dlg/Pins/Mud complex to orient the spindle in opposite directions in distinct cell types
Zhang, Y. V., Raghuwanshi, R. P., Shen, W. L. and Montell, C. (2013). Food experience-induced taste desensitization modulated by the Drosophila TRPL channel. Nat Neurosci. PubMed ID: 24013593
Summary: Animals tend to reject bitter foods. However, long-term exposure to some unpalatable tastants increases acceptance of these foods. This study show that dietary exposure to an unappealing but safe additive, camphor, caused the fruit fly Drosophila melanogaster to decrease camphor rejection. The transient receptor potential-like (TRPL) cation channel was a direct target for camphor in gustatory receptor neurons, and long-term feeding on a camphor diet led to reversible downregulation of TRPL protein concentrations. The turnover of TRPL was controlled by an E3 ubiquitin ligase, Ube3a. The decline in TRPL levels and increased acceptance of camphor reversed after returning the flies to a camphor-free diet long term. It is proposed that dynamic regulation of taste receptors by ubiquitin-mediated protein degradation comprises an important molecular mechanism that allows an animal to alter its taste behavior in response to a changing food environment.
Wednesday, September 11th
Kuroki, S., et al. (2013). Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 341: 1106-1109. PubMed ID: 24009392
Developmental gene expression is defined through cross-talk between the function of transcription factors and epigenetic status, including histone modification. Although several transcription factors play crucial roles in mammalian sex determination, how epigenetic regulation contributes to this process remains unknown. This study observed Male-to-female sex reversal in mice lacking the H3K9 demethylase Jmjd1a and found that Jmjd1a regulates expression of the mammalian Y chromosome sex-determining gene Sry. Jmjd1a directly and positively controls Sry expression by regulating H3K9me2 marks (See Drosophila Histone H3). These studies reveal a pivotal role of histone demethylation in mammalian sex determination.
Yamanaka, N., Romero, N. M., Martin, F. A., Rewitz, K. F., Sun, M., O'Connor, M. B. and Leopold, P. (2013). Neuroendocrine control of Drosophila larval light preference. Science 341: 1113-1116. PubMed ID: 24009394
Animal development is coupled with innate behaviors that maximize chances of survival. This study shows that the prothoracicotropic hormone (PTTH), a neuropeptide that controls the developmental transition from juvenile stage to sexual maturation, also regulates light avoidance in Drosophila larvae. PTTH, through its receptor Torso, acts on two light sensors--the Bolwig's organ and the peripheral class IV dendritic arborization neurons--to regulate light avoidance. This study found that PTTH concomitantly promotes steroidogenesis and light avoidance at the end of larval stage, driving animals toward a darker environment to initiate the immobile maturation phase. Thus, PTTH controls the decisions of when and where animals undergo metamorphosis, optimizing conditions for adult development.
Tuesday, September 10th
Marianes, A. and Spradling, A. C. (2013). . Physiological and stem cell compartmentalization within the Drosophila midgut.Elife 2: e00886. PubMed ID: 23991285
The Drosophila midgut is maintained throughout its length by superficially similar, multipotent intestinal stem cells that generate new enterocytes and enteroendocrine cells in response to tissue requirements. This study found that the midgut shows striking regional differentiation along its anterior-posterior axis. At least ten distinct subregions differ in cell morphology, physiology and the expression of hundreds of genes with likely tissue functions. Stem cells also vary regionally in behavior and gene expression, suggesting that they contribute to midgut sub-specialization. Tumors generated by disrupting Notch signaling arose preferentially in three subregions and tumor cells also appeared to respect regional borders. Thus, apparently similar intestinal stem cells differ regionally in cell production, gene expression and in the ability to spawn tumors.
Flavell, S. W., Pokala, N., Macosko, E. Z., Albrecht, D. R., Larsch, J. and Bargmann, C. I. (2013). Serotonin and the Neuropeptide PDF Initiate and Extend Opposing Behavioral States in C. elegans. Cell 154: 1023-1035. PubMed ID: 23972393
Foraging animals have distinct exploration and exploitation behaviors that are organized into discrete behavioral states. This study characterized a neuromodulatory circuit that generates long-lasting roaming and dwelling states in C. elegans. Two opposing neuromodulators, serotonin and the neuropeptide pigment dispersing factor (PDF; see Drosophila PDF), each initiate and extend one behavioral state. Serotonin promotes dwelling states through the MOD-1 serotonin-gated chloride channel. PDF promotes roaming states through a Galphas-coupled PDF receptor (see Drosophila G protein sα 60A); optogenetic activation of cAMP production in PDF receptor-expressing cells induces prolonged roaming states. The neurons that produce and respond to each neuromodulator form a distributed circuit orthogonal to the classical wiring diagram, with several essential neurons that express each molecule. The slow temporal dynamics of this neuromodulatory circuit supplement fast motor circuits to organize long-lasting behavioral states.
Monday, September 9th
King, I. F., Yandava, C. N., Mabb, A. M., Hsiao, J. S., Huang, H. S., Pearson, B. L., Calabrese, J. M., Starmer, J., Parker, J. S., Magnuson, T., Chamberlain, S. J., Philpot, B. D. and Zylka, M. J. (2013).. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501: 58-62. PubMed ID: 23995680
Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown.This study found that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. This length-dependent effect on gene expression is due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. These findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.
Dorighi, K. M. and Tamkun, J. W.. The trithorax group proteins Kismet and ASH1 promote H3K36 dimethylation to
counteract Polycomb group repression in Drosophila. Development. PubMed ID: 24004944
Members of the Polycomb group of repressors and trithorax group of
activators maintain heritable states of transcription by modifying
nucleosomal histones or remodeling chromatin. The trithorax group protein Kismet (KIS) is related to the SWI/SNF and CHD families of chromatin remodeling factors. Evidence is presented KIS promotes transcription elongation
and counteracts Polycomb group repression via distinct mechanisms. Mutations in kis cause a global reduction in the di- and tri-methylation of histone H3 on lysine 36 (H3K36) - modifications that antagonize H3K27 methylation in vitro. Furthermore, loss of ASH1 significantly decreases H3K36 dimethylation, providing further evidence that ASH1 is an H3K36 dimethylase in vivo. These and other findings suggest that KIS antagonizes Polycomb group repression by facilitating ASH1-dependent H3K36 dimethylation.
Sunday, September 8
Ciceri, G., Dehorter, N., Sols, I., Huang, Z. J., Maravall, M. and Marin, O. (2013). Lineage-specific laminar organization of cortical GABAergic interneurons. Nat Neurosci 16: 1199-1210. PubMed ID: 23933753
Summary: In the cerebral cortex, pyramidal cells and interneurons are generated in distant germinal zones, and so the mechanisms that control their precise assembly into specific microcircuits remain an enigma. This study reports that cortical interneurons labeled at the clonal level do not distribute randomly but rather have a strong tendency to cluster in the mouse neocortex. This behavior is common to different classes of interneurons, independently of their origin. Interneuron clusters are typically contained within one or two adjacent cortical layers, are largely formed by isochronically generated neurons and populate specific layers, as revealed by unbiased hierarchical clustering methods. These results suggest that different progenitor cells give rise to interneurons populating infra- and supragranular cortical layers, which challenges current views of cortical neurogenesis. Thus, specific lineages of cortical interneurons seem to be produced to primarily mirror the laminar structure of the cerebral cortex, rather than its columnar organization.
Mazzoni, E. O., Mahony, S., Peljto, M., Patel, T., Thornton, S. R., McCuine, S., Reeder, C., Boyer, L. A., Young, R. A., Gifford, D. K. and Wichterle, H. (2013). Saltatory remodeling of Hox chromatin in response to rostrocaudal patterning signals. Nat Neurosci 16: 1191-1198. PubMed ID: 23955559
Summary: Hox genes controlling motor neuron subtype identity are expressed in rostrocaudal patterns that are spatially and temporally collinear with their chromosomal organization. This study demonstrates that Hox chromatin is subdivided into discrete domains that are controlled by rostrocaudal patterning signals that trigger rapid, domain-wide clearance of repressive histone H3 Lys27 trimethylation (H3K27me3; see Drosophila Histone H3) polycomb modifications. Treatment of differentiating mouse neural progenitors with retinoic acid leads to activation and binding of retinoic acid receptors (RARs) to the Hox1-Hox5 chromatin domains (see Drosophila Antennapedia complex) , which is followed by a rapid domain-wide removal of H3K27me3 and acquisition of cervical spinal identity. Wnt and fibroblast growth factor (FGF) signals induce expression of the Cdx2 transcription factor (see Drosophila Caudal) that binds and clears H3K27me3 from the Hox1-Hox9 chromatin domains, leading to specification of brachial or thoracic spinal identity. It is proposed that rapid clearance of repressive modifications in response to transient patterning signals encodes global rostrocaudal neural identity and that maintenance of these chromatin domains ensures the transmission of positional identity to postmitotic motor neurons later in development.
Saturday September 7th
Rodel, C. J., Gilles, A. F. and Averof, M. (2013). MicroRNAs Act as Cofactors in Bicoid-Mediated Translational Repression Curr Biol 23: 1579-1584. PubMed ID: 23910663
Summary: Noncoding RNAs have recently emerged as important regulators of mRNA translation and turnover. Nevertheless, how their function integrates with protein-mediated translational regulation is largely ignored. This study focused on Bicoid, a key patterning molecule in Drosophila, which inhibits the translation of caudal in the anterior part of the embryo. Previous work showed that Bicoid recruits the cap-binding protein d4EHP on the caudal mRNA to repress translation. This study shows that miR-2 family microRNAs are essential cofactors in the repression of caudal. This study demonstrates that Bicoid acts through a 63 nt response element in the caudal 3' UTR that includes a single miR-2 target site. Four predicted Bicoid splice isoforms are capable of caudal repression, including two that lack the d4EHP interaction domain; all four isoforms require the microRNA target for repression.The discovery that microRNAs play an essential role in Bicoid-mediated translational repression opens up new perspectives on Bicoid's function and evolution.
Flavell, S. W., Pokala, N., Macosko, E. Z., Albrecht, D. R., Larsch, J. and Bargmann, C. I. (2013). . Serotonin and the Neuropeptide PDF Initiate and Extend Opposing Behavioral States in C. elegans. Cell 154: 1023-1035. PubMed ID: 23972393
Foraging animals have distinct exploration and exploitation behaviors that are organized into discrete behavioral states. This study characterized a neuromodulatory circuit that generates long-lasting roaming and dwelling states in Caenorhabditis elegans. Two opposing neuromodulators, serotonin and the neuropeptide pigment dispersing factor (PDF; see Drosophila PDF), each initiate and extend one behavioral state. Serotonin promotes dwelling states through the MOD-1 serotonin-gated chloride channel. The spontaneous activity of serotonergic neurons correlates with dwelling behavior, and optogenetic modulation of the critical MOD-1-expressing targets induces prolonged dwelling states. PDF promotes roaming states through a Galphas-coupled PDF receptor (see Drosophila G protein salpha 60A); optogenetic activation of cAMP production in PDF receptor-expressing cells induces prolonged roaming states. The neurons that produce and respond to each neuromodulator form a distributed circuit orthogonal to the classical wiring diagram, with several essential neurons that express each molecule. The slow temporal dynamics of this neuromodulatory circuit supplement fast motor circuits to organize long-lasting behavioral states.
Friday, September 5th
Mazzoni, E. O., Mahony, S., Closser, M., Morrison, C. A., Nedelec, S., Williams, D. J., An, D., Gifford, D. K. and Wichterle, H. (2013). Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nat Neurosci 16: 1219-1227. PubMed ID: 23872598
Three transcription factors, Ngn2, Isl1 and Lhx3, are sufficient to program rapidly and efficiently spinal motor neuron identity when expressed in differentiating mouse embryonic stem cells. Replacement of Lhx3 by Phox2a leads to specification of cranial, rather than spinal, motor neurons. CHIP analysis of Isl1, Lhx3 and Phox2a binding sites revealed that the two cell fates are programmed by the recruitment of Isl1-Lhx3 and Isl1-Phox2a complexes to distinct genomic locations characterized by a unique grammar of homeodomain binding motifs. These findings suggest that synergistic interactions among transcription factors determine the specificity of their recruitment to cell type-specific binding sites and illustrate how a single transcription factor can be repurposed to program different cell types.
Ciceri, G., Dehorter, N., Sols, I., Huang, Z. J., Maravall, M. and Marin, O. (2013). Lineage-specific laminar organization of cortical GABAergic interneurons. Nat Neurosci 16: 1199-1210. PubMed ID: 23933753
In the cerebral cortex, pyramidal cells and interneurons are generated in distant germinal zones, and so the mechanisms that control their precise assembly into specific microcircuits remain an enigma. This study report sthat cortical interneurons labeled at the clonal level do not distribute randomly but rather have a strong tendency to cluster in the mouse neocortex. This behavior is common to different classes of interneurons, independently of their origin. Interneuron clusters are typically contained within one or two adjacent cortical layers, are largely formed by isochronically generated neurons and populate specific layers, as revealed by unbiased hierarchical clustering methods. These results suggest that different progenitor cells give rise to interneurons populating infra- and supragranular cortical layers, which challenges current views of cortical neurogenesis. Thus, specific lineages of cortical interneurons seem to be produced to primarily mirror the laminar structure of the cerebral cortex, rather than its columnar organization.
Thursday, July 5
McIlroy, G., Foldi, I., Aurikko, J., Wentzell, J. S., Lim, M. A., Fenton, J. C., Gay, N. J. and Hidalgo, A. (2013).. Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nat Neurosci 16: 1248-1256. PubMed ID: 23892553
Neurotrophin receptors corresponding to vertebrate Trk, p75(NTR) or Sortilin have not been identified in Drosophila, thus it is unknown how neurotrophism may be implemented in insects. Two Drosophila neurotrophins, DNT1 and DNT2 (Spatzle 5), have nervous system functions, but their receptors are unknown. The Toll receptor superfamily has ancient evolutionary origins and a universal function in innate immunity. This study shows that Toll paralogs unrelated to the mammalian neurotrophin receptors function as neurotrophin receptors in fruit flies. Toll-6 and Toll-7 are expressed in the CNS throughout development and regulate locomotion, motor axon targeting and neuronal survival. DNT1 and DNT2 interact genetically with Toll-6 and Toll-7, and DNT1 and DNT2 bind to Toll-6 and Toll-7 promiscuously and are distributed in vivo in domains complementary to or overlapping with those of Toll-6 and Toll-7. It is concluded that in fruit flies, Tolls are not only involved in development and immunity but also in neurotrophism, revealing an unforeseen relationship between the neurotrophin and Toll protein families.
Nair, I. S., Rodrigues, V., Reichert, H. and Vijayraghavan, K. (2013). The zinc finger transcription factor Jing is required for dendrite/axonal targeting in Drosophila antennal lobe development. Dev Biol 381: 17-27. PubMed ID: 23810656
This study identified the zinc finger transcription factor Jing as being required for both for dendrite targeting of projection neurons and local interneurons as well as for axonal targeting of olfactory sensory neurons in Drosophila olfactory system development. Jing is widely expressed in the neural cells during postembryonic development. Jing loss-of-function results in loss of innervation in specific glomeruli, ectopic innervation of inappropriate glomeruli, aberrant profuse dendrite arborisation throughout the antennal lobe, as well as mistargeting to other parts of the CNS. Taken together, these findings indicate that Jing acts as a key transcriptional control element in wiring of the circuitry in the developing olfactory sensory system in Drosophila.
Wednesday, September 4
Lancaster, M. A., Renner, M., Martin, C. A., Wenzel, D., Bicknell, L. S., Hurles, M. E., Homfray, T., Penninger, J. M., Jackson, A. P. and Knoblich, J. A. (2013). Cerebral organoids model human brain development and microcephaly. Nature. PubMed ID: 23995685
Summary: A human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, has been developed that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. RNAi interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. Premature neuronal differentiation was demonstrated in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.
Juang, B. T., Gu, C., Starnes, L., Palladino, F., Goga, A., Kennedy, S. and L'Etoile N, D. (2013).. Endogenous Nuclear RNAi Mediates Behavioral Adaptation to Odor. Cell 154: 1010-1022. PubMed ID: 23993094
Summary: The purpose of somatic endogenous siRNAs (endo-siRNAs) has remained unclear. This study shows that the endo-siRNA pathway promotes odor adaptation in C. elegans AWC olfactory neurons. In adaptation, the nuclear Argonaute NRDE-3 (see Drosophila Argonaute), which acts in AWC, is loaded with siRNAs targeting odr-1, a gene whose downregulation is required for adaptation. Concomitant with increased odr-1 siRNA in AWC, increased binding of the HP1 homolog HPL-2 (Drosophila homolog; HP1) at the odr-1 locus in AWC and reduced odr-1 mRNA were observed in adapted animals. Phosphorylation of HPL-2, an in vitro substrate of the EGL-4 kinase that promotes adaption, is necessary and sufficient for behavioral adaptation. Thus, environmental stimulation amplifies an endo-siRNA negative feedback loop to dynamically repress cognate gene expression and shape behavior. This class of siRNA may act broadly as a rheostat allowing prolonged stimulation to dampen gene expression and promote cellular memory formation.
Tuesday, September 3
Abramsson, A., Kettunen, P., Banote, R. K., Lott, E., Li, M., Arner, A. and Zetterberg, H. (2013). The zebrafish amyloid precursor protein-β is required for motor neuron guidance and synapse formation. Dev Biol 381: 377-388. PubMed ID: 23850871
The amyloid precursor protein (APP: see Drosophila Appl) is a transmembrane protein mostly recognized for its association with Alzheimer's disease. The zebrafish APP homologue, appb, is expressed in post-mitotic neurons in the spinal cord. Knockdown of appb by 50–60% results in a behavioral phenotype with increased spontaneous coiling and prolonged touch-induced activity. The spinal cord motor neurons in these embryos show defective formation and axonal outgrowth patterning. Reduction in Appb also results in patterning defects and changed density of pre- and post-synapses in the neuromuscular junctions (see Drosophila neuromuscular junctions). Together, these data show that development of functional locomotion in zebrafish depends on a critical role of Appb in the patterning of motor neurons and neuromuscular junctions.
Hsiao, H. Y., Jukam, D., Johnston, R. and Desplan, C. (2013). The neuronal transcription factor erect wing regulates specification and maintenance of Drosophila R8 photoreceptor subtypes . Dev Biol 381: 482-490. PubMed ID: 23850772
A double negative feedback loop between the Warts kinase of the Hippo pathway and the PH-domain growth regulator Melted regulates the choice in photoreceptor cell fate between 'pale' R8 (pR8) fate defined by Rh5 expression and 'yellow' R8 (yR8) fate characterized by Rh6 expression. The Drosophila gene encoding the homolog of human Nuclear respiratory factor 1, erect wing (ewg), is autonomously required to inhibit warts expression and to promote melted expression to specify pR8 subtype fate and induce Rh5. ewg mutants express Rh6 in most R8s due to ectopic warts expression. Further, ewg is continuously required to maintain repression of Rh6 in pR8s in aging flies. This work shows that Ewg is a critical factor for the stable down-regulation of Hippo pathway activity to determine neuronal subtype fates. Neural-enriched factors, such as Ewg, may generally contribute to the contextual re-use of signaling pathways in post-mitotic neurons.
Monday, September 2nd
Magny, E. G., Pueyo, J. I., Pearl, F. M., Cespedes, M. A., Niven, J. E., Bishop, S. A. and Couso, J. P. (2013). Conserved Regulation of Cardiac Calcium Uptake by Peptides Encoded in Small Open Reading Frames Science. PubMed ID: 23970561
Small Open Reading Frames (smORFs) are short DNA sequences able to encode small peptides of less than 100 amino acids. Study of these elements has been neglected despite thousands existing in our genomes. Peptides as short as 11 amino acids are translated and provide essential functions during insect development. This study describes two peptides of less than 30 amino acids regulating calcium transport, and hence influencing regular muscle contraction, in the Drosophila heart. These peptides seem conserved for more than 550 million years in a range of species from flies to humans, where they have been implicated in cardiac pathologies. Such conservation suggests that the mechanisms for heart regulation are ancient and that smORFs may be a fundamental genome component that should be studied systematically.
Goh, L. H., Zhou, X., Lee, M. C., Lin, S., Wang, H., Luo, Y. and Yang, X. (2013). Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains. Dev Biol 381: 353-364. PubMed ID: 23835532
Summary: During neuroblast asymmetric division, atypical Protein Kinase C (aPKC) activity is tightly regulated; aberrant levels of activity could result in tumorigenesis in third instar larval brain. This study identified clueless (clu), a genetic interactor of parkin (park), as a novel regulator of aPKC activity. Interestingly, the phenotype of the park mutant, which causes Parkinson's Disease-like symptoms in adult flies, is reminiscent of that of clu in neuroblast asymmetric division. This study provides the first clue for the potential missing pathological link between temporally separated neurogenesis and neurodegeneration events; the minor defects during early neurogenesis could be a susceptible factor contributing to neurodegenerative diseases at later stages of life.
Sunday September 1st
Ni, L., Bronk, P., Chang, E. C., Lowell, A. M., Flam, J. O., Panzano, V. C., Theobald, D. L., Griffith, L. C. and Garrity, P. A. (2013). A gustatory receptor paralogue controls rapid warmth avoidance in Drosophila. . Nature 500: 580-584. PubMed ID: 23925112
The ion channel TRPA1 is used as an internal temperature sensor in Drosophila to control the slow response of flies to shallow thermal gradients. This study shows that the rapid response of flies to steep warming gradients relies on a different protein, GR28B, providing the first example of a thermosensory role for a gustatory receptor. At the molecular level, GR28B misexpression confers thermosensitivity upon diverse cell types, suggesting that it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors reminiscent of thermoregulatory systems in larger, endothermic animals. The use of multiple, distinct molecules to respond to a given temperature may facilitate independent tuning of an animal's distinct thermosensory responses.
Chan, J. P., Staab, T. A., Wang, H., Mazzasette, C., Butte, Z. and Sieburth, D. (2013). Extrasynaptic Muscarinic Acetylcholine Receptors on Neuronal Cell Bodies Regulate Presynaptic Function in Caenorhabditis elegans. J Neurosci 33: 14146-14159. PubMed ID: 23986249
Acetylcholine (ACh) is a potent neuromodulator in the brain, and its effects on cognition and memory formation are largely performed through muscarinic acetylcholine receptors (mAChRs). mAChRs are often preferentially distributed on specialized membrane regions in neurons, but the significance of mAChR localization in modulating neuronal function is not known. This study shows that the C. elegans homolog of the M1/M3/M5 family of mAChRs, gar-3, is expressed in cholinergic motor neurons, and GAR-3-GFP fusion proteins localize to cell bodies where they are enriched at extrasynaptic regions that are in contact with the basal lamina. GAR-3 can be activated by endogenously produced ACh released from neurons that do not directly contact cholinergic motor neurons. Together, these results suggest that humoral activation of asymmetrically localized mAChRs by ACh is an evolutionarily conserved mechanism by which ACh modulates neuronal function