InteractiveFly: GeneBrief

Syncrip: Biological Overview | References

Gene name - Syncrip

Synonyms -

Cytological map position - 92F12-93A1

Function - mRNA binding protein

Keywords - localized translation during synaptic plasticity in the neuromuscular junction, regulation of synaptic output through regulation of retrograde BMP signaling, regulation of localized transcripts during axis specification

Symbol - Syp

FlyBase ID: FBgn0038826

Genetic map position - chr3R:16,582,714-16,636,543

Classification - RNA recognition motif 2 in heterogeneous nuclear ribonucleoprotein R (hnRNP R) and similar proteins

Cellular location - cytoplasm

NCBI links: Precomputed BLAST | EntrezGene
Recent literature
Ren, Q., Yang, C. P., Liu, Z., Sugino, K., Mok, K., He, Y., Ito, M., Nern, A., Otsuna, H. and Lee, T. (2017). Stem cell-intrinsic, Seven-up-triggered temporal factor gradients diversify intermediate neural progenitors. Curr Biol [Epub ahead of print]. PubMed ID: 28434858
Building a sizable, complex brain requires both cellular expansion and diversification. One mechanism to achieve these goals is production of multiple transiently amplifying intermediate neural progenitors (INPs) from a single neural stem cell. Like mammalian neural stem cells, Drosophila type II neuroblasts utilize INPs to produce neurons and glia. Within a given lineage, the consecutively born INPs produce morphologically distinct progeny, presumably due to differential inheritance of temporal factors. To uncover the underlying temporal fating mechanisms, type II neuroblasts' transcriptome was profiled across time. The results reveal opposing temporal gradients of Imp and Syp RNA-binding proteins (descending and ascending, respectively). Maintaining high Imp throughout serial INP production expands the number of neurons and glia with early temporal fate at the expense of cells with late fate. Conversely, precocious upregulation of Syp reduces the number of cells with early fate. Furthermore, this study reveals that the transcription factor Seven-up initiates progression of the Imp/Syp gradients. Interestingly, neuroblasts that maintain initial Imp/Syp levels can still yield progeny with a small range of early fates. It is therefore proposed that the Seven-up-initiated Imp/Syp gradients create coarse temporal windows within type II neuroblasts to pattern INPs, which subsequently undergo fine-tuned subtemporal patterning.
Pahl, M. C., Doyle, S. E. and Siegrist, S. E. (2019). E93 integrates neuroblast intrinsic state with developmental time to terminate MB neurogenesis via autophagy. Curr Biol 29(5): 750-762. PubMed ID: 30773368
Most neurogenesis occurs during development, driven by the cell divisions of neural stem cells (NSCs). This study used Drosophila to understand how neurogenesis terminates once development is complete, a process critical for neural circuit formation. E93 was identified as a steroid-hormone-induced transcription factor that downregulates phosphatidylinositol 3-kinase (PI3K) levels to activate autophagy for elimination of mushroom body (MB) neuroblasts. MB neuroblasts are a subset of Drosophila NSCs that generate neurons important for memory and learning. MB neurogenesis extends into adulthood when E93 is reduced and terminates prematurely when E93 is overexpressed. E93 is expressed in MB neuroblasts during later stages of pupal development only, which includes the time when MB neuroblasts normally terminate their divisions. Cell intrinsic Imp and Syp temporal factors regulate timing of E93 expression in MB neuroblasts, and extrinsic steroid hormone receptor (EcR) activation boosts E93 levels high for termination. Imp inhibits premature expression of E93 in a Syp-dependent manner, and Syp positively regulates E93 to promote neurogenesis termination. Imp and Syp together with E93 form a temporal cassette, which consequently links early developmental neurogenesis with termination. Altogether, E93 functions as a late-acting temporal factor integrating extrinsic hormonal cues linked to developmental timing with neuroblast intrinsic temporal cues to precisely time neurogenesis ending during development.

Localized mRNA translation is thought to play a key role in synaptic plasticity, but the identity of the transcripts and the molecular mechanism underlying their function are still poorly understood. This study shows that Syncrip, a regulator of localized translation in the Drosophila oocyte and a component of mammalian neuronal mRNA granules, is also expressed in the Drosophila larval neuromuscular junction, where it regulates synaptic growth. RNA-immunoprecipitation followed by high-throughput sequencing and qRT-PCR were used to show that Syncrip associates with a number of mRNAs encoding proteins with key synaptic functions, including msp-300, syd-1, neurexin-1, futsch, highwire, discs large, and alpha-spectrin. The protein levels of MSP-300, Discs large, and a number of others are significantly affected in syncrip null mutants. Furthermore, syncrip mutants show a reduction in MSP-300 protein levels and defects in muscle nuclear distribution characteristic of msp-300 mutants. These results highlight a number of potential new players in localized translation during synaptic plasticity in the neuromuscular junction. It is proposed that Syncrip acts as a modulator of synaptic plasticity by regulating the translation of these key mRNAs encoding synaptic scaffolding proteins and other important components involved in synaptic growth and function (McDermott, 2014).

Localized translation is a widespread and evolutionarily ancient strategy used to temporally and spatially restrict specific proteins to their site of function and has been extensively studied during early development and in polarized cells in a variety of model systems. It is thought to be of particular importance in the regulation of neuronal development and in the plastic changes at neuronal synapses that underlie memory and learning, allowing rapid local changes in gene expression to occur independently of new transcriptional programs. The Drosophila neuromuscular junction (NMJ) is an excellent model system for studying the general molecular principles of the regulation of synaptic development and plasticity. Genetic or activity-based manipulations of synaptic translation at the NMJ has previously been shown to affect the morphological and electrophysiological plasticity of NMJ synapses. However, neither the mRNA targets nor the molecular mechanism by which such translational regulation occurs are fully understood (McDermott, 2014).

Previously work identified CG17838, the fly homolog of the mammalian RNA binding protein SYNCRIP/hnRNPQ, which was named Syncrip (Syp). Mammalian SYNCRIP/hnRNPQ is a component of neuronal RNA transport granules that contain CamKIIα, Arc, and IP3R1 mRNAs (Bannai, 2004; Kanai, 2004; Elvira, 2006) and is thought to regulate translation via an interaction with the noncoding RNA BC200/BC1, itself a translational repressor (Duning, 2008). Moreover, SYNCRIP/hnRNPQ competes with poly(A) binding proteins to inhibit translation in vitro (Svitkin, 2013) and regulates dendritic morphology (Chen, 2012) via association with, and localization of, mRNAs encoding components of the Cdc-42/N-WASP/Arp2/3 actin nucleation-promoting complex. Drosophila Syp has a domain structure similar to its mammalian homolog, containing RRM RNA binding domains and nuclear localization signal(s), as well as encoding a number of protein isoforms. It was previously shown that Syp binds specifically to the gurken (grk) mRNA localization signal together with a number of factors previously shown to be required for grk mRNA localization and translational regulation (McDermott, 2012). Furthermore, syp loss-of-function alleles lead to patterning defects indicating that syp is required for grk and oskar (osk) mRNA localization and translational regulation in the Drosophila oocyte (McDermott, 2014).

This study shows that Syp is detected in the Drosophila third instar larval muscle nuclei and also postsynaptically at the NMJ. Syp is required for proper synaptic morphology at the NMJ, as syp loss-of-function mutants show a synaptic overgrowth phenotype, while overexpression of Syp in the muscle can suppress NMJ growth. Syp protein associates with a number of mRNAs encoding proteins with key roles in synaptic growth and function including, msp-300, syd-1, neurexin-1 (nrx-1), futsch, highwire (hiw), discs large 1 (dlg1), and α-spectrin (α-spec). The protein levels of a number of these mRNA targets, including msp-300 and dlg1, are significantly affected in syp null mutants. Furthermore, in addition to regulating MSP-300 protein levels, Syp is required for correct MSP-300 protein localization, and syp null mutants have defects in myonuclear distribution and morphology that resemble those observed in msp-300 mutants. It is proposed that Syp coordinates the protein levels from a number of transcripts with key roles in synaptic growth and is a mediator of synaptic morphology and growth at the Drosophila NMJ (McDermott, 2014).

The results demonstrate that Syp is required for the appropriate branching of the motoneurons and the number of synapses they make at the muscle. These observations are potentially explained by the finding that Syp is also required for the correct level of expression of msp-300, dlg1 and other mRNA targets. Given that it was previously shown that Syp regulates mRNA localization and localized translation in the Drosophila oocyte (McDermott, 2012), and studies by others have shown that mammalian SYNCRIP/hnRNPQ inhibits translation initiation by competitively binding poly(A) sequences (Svitkin, 2013), these functions of Syp as occurring at the level of translational regulation of the mRNAs to which Syp binds. The data are also consistent with other work in mammals showing that SYNCRIP/hnRNPQ is a component of neuronal RNA transport granules (Bannai, 2004; Kanai, 2004; Elvira, 2006) that can regulate dendritic morphology via the localized expression of mRNAs encoding components of the Cdc-42/N-WASP/Arp2/3 actin nucleation-promoting complex (Chen, 2012; McDermott, 2014 and references therein).

Translation at the Drosophila NMJ is thought to provide a mechanism for the rapid assembly of synaptic components and synaptic growth during larval development, in response to rapid increases in the surface area of body wall muscles or in response to changes in larval locomotion. The phenotypes observed in this study resemble, and are comparable to, those seen when subsynaptic translation is altered genetically or by increased locomotor activity. In syp null mutants, NMJ synaptic terminals are overgrown, containing more branches and synaptic boutons. Similarly, bouton numbers are increased by knocking down Syp in the muscle using RNAi. In contrast, overexpression of Syp in the muscle has the opposite phenotype, resulting in an inhibition of synaptic growth and branching. Furthermore, expressing RNAi against syp in motoneurons alone does not result in a change in NMJ morphology, indicating that Syp acts postsynaptically in muscle, but not presynaptically at the NMJ to regulate morphology. Interestingly, pan-neuronal syp knockdown or overexpression using Elav-GAL4 also results in NMJ growth defects, revealing that some of the defects observed in the syp null mutant may be attributed to Syp function in neuronal cell types other than the motoneurons, such as glial cells, which are known to influence NMJ morphology. Finally, while Syp is not required in the motoneuron to regulate synapse growth and is not detected in the motoneuron, the possibility cannot be excluded that Syp is present at low levels in the presynapse and regulates processes independent of synapse morphology. A further detailed characterization of the cell types and developmental stages in which Syp is expressed and functions is required to better understand the complex phenotypes that were observe (McDermott, 2014).

RNA binding proteins have emerged as critical regulators of both neuronal morphology and synaptic transmision, suggesting that protein production modulates synapse efficacy. Consistent with this, it has been shown in a parallel study that Syp is required for proper synaptic transmission and vesicle release and regulates the presynapse through expression of retrograde Bone Morphogenesis Protein (BMP) signals in the postsynapse (Halstead, 2014). In this role, Syp may coordinate postsynaptic translation with presynaptic neurotransmitter release. These observations provide a good explanation for how Syp influences the presynapse despite being only detectable in the postsynapse. This study has shown that Syp associates with a large number of mRNAs within third instar larvae, many of which encode proteins with key roles in synaptic growth and function. Syp mRNA targets include msp-300, syd-1, nrx-1, futsch, hiw, dlg1, and α-spec. Syp negatively regulates Syd-1, Hiw, and DLG protein levels in the larval body wall but positively regulates MSP-300 and Nrx-1 protein levels. Dysregulation of these multiple mRNA targets likely accounts for the phenotypes that were observed. Postsynaptically expressed targets with key synaptic roles that could explain the synaptic phenotypes that were observed in syp alleles include MSP-300, α-Spec, and DLG. For example, mutants in dlg1 and mutants where postsynaptic DLG is destabilized or delocalized have NMJ morphology phenotypes similar to those observed upon overexpression of Syp in the muscle. Presynaptically expressed targets include syd-1, nrx-1, and hiw. However, this study has shown that syp knockdown in presynaptic motoneurons does not result in any defects in NMJ morphology. The RIP-Seq experiments were carried out using whole larvae and will, therefore, identify Syp targets in a range of different tissues and cells, the regulation of which may or may not contribute to the phenotype that were observed in syp mutants. It is, therefore, possible that Syp associates with these presynaptic targets in other neuronal cell types such as the DA neurons of the larval peripheral nervous system. It is also possible that Nrx-1 or Hiw are expressed and required postsynaptically in the muscle, but this has not been definitively determined. syp alleles may provide useful tools to examine where key synaptic genes are expressed and how they are regulated (McDermott, 2014).

The identity of localized mRNAs and the mechanism of localized translation at the NMJ are major outstanding questions in the field. To date, studies have shown that GluRIIA mRNA aggregates are distributed throughout the muscle. The Syp targets identified in this study, such as msp-300, hiw, nrx-1, α-spec, and dlg1, are now excellent candidates for localized expression at the NMJ. Ultimately, conclusive demonstration of localized translation will involve the visualization of new protein synthesis of targets during activity-dependent synaptic plasticity. Biochemical experiments will also be required to establish the precise mode of binding of Syp to its downstream mRNA targets, the basis for interaction specificity, and the molecular mechanism by which Syp differentially regulates the protein levels of its mRNA targets at the Drosophila NMJ. Despite the fact that mammalian SYNCRIP is known to associate with poly(A) tails, this study and other published work have revealed that Syp can associate with specific transcripts (Chen, 2012; McDermott, 2012). How Syp associates with specific mRNAs is unknown, and future studies are needed to uncover whether the interaction of Syp with specific transcripts is dictated by direct binding of the three Syp RRM RNA binding domains or by binding to other specific mRNA binding proteins. It is also possible that specific mRNA stem–loops, similar to the gurken localization signal, are required for Syp to bind to its mRNA targets (McDermott, 2014).

This study shows that msp-300 is the most significant mRNA target of Syp. MSP-300 is the Drosophila ortholog of human Nesprin proteins. These proteins have been genetically implicated in various human myopathies. For example, Nesprin/Syne-1 or Nesprin/Syne-2 is associated with Emery-Dreifuss muscular dystrophy (EDMD) (Puckelwartz, 2009) as well as severe cardiomyopathies (Puckelwartz, 2010). Moreover, Syp itself is increasingly linked with factors and targets that can cause human neurodegenerative disorders. Recent work has revealed that SYNCRIP/hnRNPQ and Fragile X mental retardation protein (FMRP) are present in the same mRNP granule (Chen, 2012), and loss of expression of FMRP or the ability of FMRP to interact with mRNA and polysomes can cause cases of Fragile X syndrome. Separate studies have also shown that SYNCRIP interacts with wild-type survival of motor neuron (SMN) protein but not the truncated or mutant forms found to cause spinal muscular atrophy (Rossoll, 2002), and Syp genetically interacts with Smn mutations in vivo (Sen, 2013). Understanding Syp function in the regulation of such diverse and complex targets may, therefore, provide new avenues for understanding the molecular basis of complex disease phenotypes and potentially lead to future therapeutic approaches (McDermott, 2014).

Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse

Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. This study identified the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. Syncrip influences the levels of the bone morphogenic protein ligand Glass bottom boat from the post-synapse and regulates the pre-synapse. These results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, it is proposed that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation (Halstead, 2014).

Neuronal communication depends on the release of neurotransmitters from the pre-synaptic terminal that causes rapid depolarization in the postsynaptic cell. In tandem, retrograde signals emanating from the post-synapse signal back to the pre-synapse. These signals modulate synaptic output through changes in the structure and function of the pre-synaptic terminals. The retrograde signals in flies are crucial for regulating local synaptic strength during development). In mammalian central neurons, the release of retrograde signals from the dendrites has been implicated in long term potentiation and synapse growth. However, despite their importance, relatively few factors are known to regulate the expression of retrograde signals, and little is known about how retrograde signaling is coordinated with other synaptic processes, such as local translation (Halstead, 2014).

The Drosophila third instar neuromuscular junction (NMJ) is an excellent model to study synaptic function and significant progress has been made in discovering some of the players involved in retrograde signaling. The rapid growth of the muscle during the larval stage requires a concomitant expansion of the neuromuscular synapse to maintain contraction efficacy. The ability to correlate changes on either side of the synapse with neuronal activity has revealed that retrograde signaling regulates plastic growth and homeostasis at the larval NMJ. While the details of the retrograde signaling pathway has remained elusive, genetic and pharmacological studies have implicated calcium signaling, nuclear import pathways, presynaptic exosome secretion, postsynaptic vesicle trafficking via Synaptotagmin family members, and Bone Morphogenic Protein growth factor secretion (Halstead, 2014 and references therein).

The Bone Morphogenic Protein (BMP) pathway contains members of the conserved transforming growth factor β (TGF-β) family and is one of the best characterized retrograde signaling pathways. The retrograde BMP ligand, Glass bottom boat (Gbb) is secreted from the muscle and received by presynaptic receptors, which in turn phosphorylate the transcription factor Mothers against decapentaplegic (Mad) and interact with LIM kinase 1, which act in tandem to contribute to presynaptic stability and growth. P-Mad is then trafficked to the neuron nucleus where it programs transcription. BMP retrograde signaling serves to stabilise synapse structure and neurotransmission. This conserved signaling pathway is central to the development and function of synapses, and misregulation is associated with a number of diseases. Despite this, little is known about the factors that serve to regulate the BMP signaling pathway and coordinate it with other processes in the synapse (Halstead, 2014).

Genetic studies suggest that retrograde signaling proceeds through a complex pathway involving multiple processes. However, one class of gene that has not been well examined in retrograde signaling are the RNA-binding proteins (RBPs). This is surprising, as RBPs are highly expressed in neuronal tissues and are known to be central to the long-term changes that facilitate synapse plasticity through localised translation . Moreover, recent genome-wide analysis has revealed that RBPs can participate in multiple cell processes auxiliary to mRNA metabolism (Halstead, 2014).

This study has identified a new factor in retrograde signaling, Syncrip (Syp), which is required in the muscle to influence vesicle release and membrane integrity pre-synaptically. Syp is the fly homolog of hnRNP Q/SYNaptotagmin-binding Cytoplasmic RNA-Interacting Protein (SYNCRIP) and is a highly conserved heterogenous nuclear ribonucleoprotein (hnRNP). This study identified Syp in a biochemical screen for proteins that associate with the gurken localization signal (Van De Bor, 2005), an RNA signal that is necessary and sufficient for the localization of gurken mRNA to determine axial polarity in the oocyte and future embryo. Syp was found to be required for mRNA localization and local translation of gurken mRNA in oogenesis. Syp has also been detected in mammalian dendrites, where it is found in trafficked RNP granules containing mRNAs encoding synaptic receptors and non-coding regulatory RNAs (Duning, 2008; Bannai, 2004). Moreover, in vitro, mammalian SYNCRIP competes with Poly(A) binding proteins to inhibit translation (Svitkin, 2013) and is required to regulate dendritic morphology (Chen, 2012; Halstead, 2014 and references therein).

This study shows that Drosophila Syp is present in the muscle and required for correct vesicle biogenesis, docking, and neurotransmitter release from the pre-synapse. This unexpected non-autonomous requirement for an RNA binding protein is explained by the fact that Syp is necessary for the correct levels of the canonical BMP signaling pathway in both muscle and neuron. Upregulation of BMP signaling in syp mutants was shown to correlate with aberrant synapse structure and function. This results suggest that the conserved RNA binding protein Syp regulates synaptic output via retrograde signaling. Given that Syp is thought to have a known role in regulating translation, it is proposed that Syp serves to coordinate synaptic efficacy through retrograde signaling with postsynaptic localised translation (Halstead, 2014).

The results highlight the conserved mRNA-binding protein Syp as a novel factor required in the post-synapse for the modulation of synaptic output in the pre-synapse. During synaptic plasticity, neurotransmitter released from the pre-synapse is thought to signal changes in protein production at the post-synapse, which modulates the structure and efficacy of the post-synapse. In the reverse direction, retrograde signals from the postsynapse are thought to signal back to regulate the structure and the rate of secretion from the pre-synapse. Despite their importance, little is known about how these two processes are balanced and coordinated across the synapse during development and synaptic plasticity, which is crucial for memory and learning. This study has identified the RNA binding protein Syp as a new factor that influences both these processes. Given that the mammalian homologues of Drosophila syp (SYNCRIP/hnRNP Q1 and 2) restricts translation in both neuronal and non-neuronal cells (Chen, 2012; Svitkin, 2013), a model was proposed in which Syp co-ordinates translation in the post-synapse with retrograde signaling to the pre-synapse, thus fine-tuning both sides of the synapse. In support of this model, loss of Syp was found to lead to an upregulation of retrograde signaling factors. syp mutants also show enlarged post synaptic densities and a dramatic decrease in the rate of presynaptic vesicle release. In addition, in a parallel study it was revealed that Syp is genetically required only in the muscle to regulate NMJ morphology (McDermott, 2014), since loss of Syp leads to synapse overgrowth and over expression of Syp leads to synapse undergrowth. While the possibility that Syp also has a role in the motoneuron cannot be completely excluded, this seems unlikely. First, Syp protein cannot be detected in the motoneuron and second, RNAi depletion experiments show that Syp is only required postsynaptically and not presynaptically for correct NMJ morphology (Halstead, 2014).

Previous genetic studies have revealed a well characterised pathway for Gbb retrograde signaling. Loss of Glass bottom boat leads to NMJ undergrowth, defects in the integrity of the synaptic membrane, vesicle size, and a decrease in synaptic output, and many of these phenotypes are rescued by expression of Gbb expression in muscle. Accordingly, loss of the presynaptic Gbb receptors, Wishful thinking and Thick veins, and the downstream R-smads, also lead to similar phenotypes. Together these studies show that a decreased in Gbb signalling leads to synapse undergrowth and decrease in synaptic output. The results support a role for Syp in lowering Gbb retrograde signalling, since in syp mutants Gbb protein is elevated and the NMJ synapse is overgrown. However, one aspect of the syp phenotype that does not fit this model is a reduction in the efficiency of vesicle release, which is the opposite of that expected from an increase in Gbb signaling. There are several possible explanations to this discrepancy. While the phenotype of Gbb loss of function has been characterised in detail, overexpression of Gbb has only been used to rescue mutant phenotypes. It is therefore possible that overexpression of Gbb and P-MAD leads to similar effects on vesicle release as the loss of Gbb function. Consistent with this possibility, disruption of the ubiquitin ligase Highwire leads to upregulation of BMP signalling, and to a decrease in synaptic transmission and NMJ overgrowth similar to syncrip mutants. Another possibility is that syp could also be influencing the pre-synapse through roles in other cell types. Supporting this idea is the fact that Syp is present and required in many tissues, has many downstream targets (McDermott, 2014) and its mechanism of action is likely to be different in different individual targets and tissues. Syp could therefore influence vesicle release efficiency in the motorneurons through a role in glia or interneurons. Finally, in a parallel study, immunoprecipitation of Syp was performed followed by high-throughput sequencing to assess the RNA binding partners of Syp (McDermott, 2014). Syp associates with multiple transcripts encoding key synaptic regulators, as well as many mRNAs encoding proteins of unknown function. While Syp does not associate with glass bottom boat mRNA, it is quite possible that it regulates the BMP pathway by binding an mRNA encoding one of the pathway's many other components, a novel BMP regulator, or indeed a previously undiscovered parallel retrograde signalling pathway (Halstead, 2014).

Adding to the complexity of Syp's function, both mammalian SYNCRIP and Drosophila Syp contain three canonical RNA binding domains, RNA recognition motifs (RRMs), which are known to sometimes bind proteins as well as RNA and mammalian SYNCRIP contains an additional RGG/RG rich C-terminal domain that is likely to interact with proteins. This domain is thought to promote interaction between mammalian SYNCRIP and multiple Synaptotagmins in vitro through their common C2B domain (Mizutani, 2000). While there are 15 known vertebrate Synaptotagmins, only two (Syt 4 and 7) are expressed in the Drosophila third instar larval muscle. Intriguingly, vesicle trafficking by Synaptotagmin 4 at the postsynapse has been implicated in retrograde signaling in both flies and mammals, while the role of Syt 7 is less clear. As a result, Synaptotagmin 4 may seem an attractive candidate to interact with Drosophila Syp. Inspection of the syp gene however shows that Drosophila Syp lacks the 161 amino acid C-terminal domain found in mammalian SYNCRIP that is both necessary and sufficient for association with the Synaptotagmin C2B domain. The Synaptotagmin-interacting domain in mammalian SYNCRIP is rich in RGG/RG motifs, which can facilitate protein–protein interaction. However, while Syp's RRM domains are highly conserved between mammals and flies, Drosophila Syp contains no canonical RGG/RG motifs. Moreover, genome-wide searches for canonical RGG/RG motifs in flies and mammals detect mammalian SYNCRIP/hnRNP Q and R, but not Drosophila Syp. It is therefore unlikely that Syp mediates retrograde signaling through interaction with Synaptotagmins, though further analysis is required to rule this out conclusively (Halstead, 2014).

Interestingly, mammalian SYNCRIP has been shown to bind polyA sequences and interact with polyA binding protein (PABP) (Svitkin, 2013). PABP interacts with a wide variety of different complexes, including the microRNA-induced silencing complex (miRISC), to serve as a key regulator of global translation. Moreover, PABP has been shown to accumulate at the NMJ post-synapse to promote experience-dependent local translation that alters the efficacy of the synapse. Owing to the enrichment of Syp at the NMJ post-synapse, it is possible that Syp regulates the local expression of key members of the BMP pathway through interaction with the poly(A) tail. However, other studies have revealed Syp discriminates between different mRNAs and associates with specific transcripts (McDermott, 2012; McDermott, 2014; Chen, 2012). As loss of Syp leads to enlargement of the post synaptic densities, Syp may act to restrict translation of specific mRNAs encoding key synaptic proteins. The precise mechanism through which Syp binds specific mRNAs is unknown, but a greater understanding of the in vivo mRNA targets of Syp is likely to reveal common sequences or RNA structures, as well as identifying potential key regulatory targets for localised translation (Halstead, 2014).

In linking retrograde signaling to translation in the postsynaptic compartment, Syp fits with a growing body of evidence showing a role for RNA-binding proteins in integrating RNA metabolism with other key cellular processes. Through interaction with multiple mRNAs and possibly protein targets, Syp could integrate a number of different synaptic processes. Indeed, it is proposed that there are clear advantages for integrating trans-synaptic signaling with postsynaptic translation to balance output on both sides of the synapse. It is interesting to consider that other RBPs central to neurobiology may also be 'moonlighting' in seemingly unrelated processes. This diverse repertoire of RBP functions may explain why mutations in RBPs often lead to neurodegenerative diseases with complex phenotypes. One such highly complex disease phenotype is caused by Fragile X mental retardation protein (FMRP), which interacts with many mRNAs directly. Interestingly, recent work has also revealed that Syp and FMRP are present in the same mRNP granule (Chen, 2012), although they do not interact directly. Furthermore, separate studies have revealed that SYNCRIP binds with wildtype Survival of Motor Neuron (SMN) protein, but not the truncated or mutants forms found in Spinal Muscular Atrophy, and Syp genetically interacts with Smn mutations in vivo (Sen, 2013). While the functional significance of Syp's diverse interactions is not yet fully clear, such data highlight that Syp, like many other RBPs, has an elaborate set of molecular interactions that lead to a complex phenotype when the gene is mutated (Halstead, 2014).

While multiple studies have detected SYNCRIP in the dendrites of mammalian neurons, and experiments in cell culture have revealed the protein as a regulator of translation, the exact in vivo role of SYNCRIP remains untested in mammals. This work highlights a new role for Syp in regulating synapse function and BMP signaling in Drosophila. Given the high degree of similarity between Drosophila and mammalian Syp, the importance of BMP signaling in multiple human diseases and the well conserved features of the Drosophila NMJ as an in vivo model to investigate BMP pathways, it seems likely that Mammalian SYNCRIP will also be shown to have important function in BMP signaling and synapse biology (Halstead, 2014).

Opposing intrinsic temporal gradients guide neural stem cell production of varied neuronal fates

Neural stem cells show age-dependent developmental potentials, as evidenced by their production of distinct neuron types at different developmental times. Drosophila neuroblasts produce long, stereotyped lineages of neurons.Factors that could regulate neural temporal fate were sought by RNA-sequencing of lineage-specific neuroblasts at various developmental times. Two RNA-binding proteins, IGF-II mRNA-binding protein (Imp) and Syncrip (Syp), were found to display opposing high-to-low and low-to-high temporal gradients with lineage-specific temporal dynamics. Imp and Syp promote early and late fates, respectively, in both a slowly progressing and a rapidly changing lineage. Imp and Syp control neuronal fates in the mushroom body lineages by regulating the temporal transcription factor Chinmo translation. Together, the opposing Imp/Syp gradients encode stem cell age, specifying multiple cell fates within a lineage (Liu, 2015).

Diverse neural stem cells produce distinct sets of specialized neurons. The suite of daughter neurons generated by common neural stem cells can further change as development progresses, which suggests that the neural stem cells themselves change over time. In Drosophila, the neuroblast, a type of neural stem cell, can bud off about 100 ganglion mother cells that each divide once to produce two, often different, daughter neurons. Mapping the serially derived neurons based on birth order/time has revealed that each individual neuroblast makes an invariant series of morphologically distinct neuronal types (Liu, 2015).

Drosophila central brain neuroblasts differ greatly in the number of neuronal types produced and the tempo at which changes occur. The four mushroom body neuroblasts divide continuously throughout larval and pupal development, but each produces only three classes of neurons. By contrast, the antennal lobe anterodorsal 1 (ALad1) neuroblast generates 22 neuronal types during larval development. Although sequential neuroblast expression of temporal transcription factors specifies neuronal cell fates in lineages of the Drosophila ventral nerve cord and optic lobes, this mechanism is not easily applied to central brain. This study analyzed fate determinants that direct neuronal diversification based on the age of the neuroblast (Liu, 2015).

Genes with age-dependent changes in expression levels throughout the life of a neuroblast could confer different temporal fates upon the neuronal daughter cells born at different times. Thus, this study aimed to find genes dynamically expressed in mushroom body and antennal lobe neuroblasts by sequencing transcriptomes over the course of larval and pupal neurogenesis. Mushroom body or antennal lobe neuroblasts were marked persistently and exclusively with green fluorescent protein (GFP) by genetic intersection and immortalization tactics. Approximately 100 GFP+ neuroblasts were isolated for each RNA/cDNA preparation. Quantitative polymerase chain reaction (qPCR) showed that known neuroblast genes, including deadpan (dpn) and asense, are enriched in mushroom body and antennal lobe neuroblasts compared with total larval brains. Samples passing this qPCR quality check were sequenced. The transcriptomes of mushroom body neuroblasts were obtained at 24, 50, and 84 hours after larval hatching (ALH), as well as 36 hours after puparium formation (APF), and the transcriptomes of antennal lobe neuroblasts at 24, 36, 50, and 84 hours ALH. The antennal lobe neuroblasts were not sequenced at 36 hours APF because they stop producing neurons around puparium formation. Also, mushroom body neuroblasts were not analyzed at 36 hours ALH because the mushroom body lineages do not undergo detectable fate or molecular changes between 24 and 50 hours ALH (Liu, 2015).

Strongly dynamic genes were defined as those with a greater than fivefold change in expression level across different time points and a maximum average abundance higher than 50 transcripts per million. Eighty-three strongly dynamic genes in the mushroom body and 63 in the antennal lobe. The two sets shared 16 genes in common. Among these 16 common genes, pncr002:3R, a putative noncoding RNA, ranks highest in absolute abundance, the importance of which remains unclear (Liu, 2015).

IGF-II mRNA-binding protein (Imp) and Syncrip (Syp), which code for two evolutionally conserved RNA-binding proteins, rank second and third in absolute abundance (McDermott, 2012; McDermott, 2014; Munro, 2006). Imp is expressed abundantly at 24 hours ALH and declines to a minimum at 84 hours ALH in antennal lobe and 36 hours APF in mushroom body neuroblasts, whereas Syp increases from minimal expression at 24 hours ALH to become one of the most abundant genes at late larval stages. Imp/Syp gradients with larger amplitudes and steeper slopes characterize antennal lobe neuroblasts, which yield more diverse neuron types at faster tempos than the mushroom body neuroblasts. Antibodies to Imp and Syp showed similar patterns in shifts of protein abundance in both mushroom body neuroblasts and neuronal daughter cells. The roles of Imp and Syp in neuronal temporal fate specification were investigated in both mushroom body and antennal lobe lineages (Liu, 2015).

The post-embryonic mushroom body neuroblasts sequentially produce γ, α'/β', and α/β neurons, which can be distinguished by a variety of markers. Fasciclin II (FasII) is expressed in the perimeter of the α/β lobes, is weakly expressed in the γ lobe, and is not expressed in the α'/β' lobes. Trio, a Dbl family protein, is expressed in the γ and α'/β' lobes. The γ neurons can also be identified in wandering larvae by expression of ecdysone receptor B1 isoform (EcR-B1). Moreover, one can predict the fate of newborn mushroom body neurons based on the protein levels of Chinmo, a known temporal transcription factor, as abundant Chinmo specifies the γ fate, weak Chinmo expression confers the α'/β' fate, and absence of Chinmo permits the α/β fates (Liu, 2015).

RNA interference (RNAi) aimed to reduce Imp expression resulted in up-regulated Syp, whereas knocking down Syp expression caused increased Imp expression. This reciprocal derepression was evident in protein and transcript content as well as phenotype. Silencing Imp triggered precocious production of α/β neurons throughout larval development; these neurons lacked EcR-B1 at the wandering larval stage and showed no Chinmo at 24 hours ALH. Imp-depleted neuroblasts ended neurogenesis prematurely: By 28 hours APF, no neuroblasts remained in the mushroom body. This resulted in small adult mushroom bodies with only α/β lobes. By contrast, silencing Syp extended the production of Chinmo-positive γ neurons through pupal development. The Syp-depleted adult mushroom bodies consisted of a single prominent γ lobe. The reciprocal temporal fate transformations were also seen in the mushroom body neuroblast clones homozygous for various Imp or Syp loss-of-function mutations. Thus, Imp specifies early γ neurons and Syp specifies late α/β neurons (Liu, 2015).

It was next asked whether prolonged coexpression of Imp and Syp can increase the number of α'/β' neurons, which are typically born at a time when Imp and Syp expression levels are similar. Ectopic induction of Imp or Syp transgenes enhanced Imp or Syp protein levels in mushroom body newborn neuronal daughter cells but not in the neuroblasts. In the case of Syp overexpression, the early larval neuroblasts still contained abundant Imp, as did their newborn neurons expressing ectopic Syp. Analogously, overexpressing Imp rendered the pupal-born neurons strongly positive for Syp as well as ectopic Imp. Therefore, after Imp or Syp overexpression, many more newborn neurons simultaneously expressed Imp and Syp, and the normally modest α'/β' neuronal lobes were enlarged in adult brains. Cell death was unlikely to distort the developmental outcomes, as rare sporadic cell death was only detected in mushroom body neurons expressing ectopic Syp at 50 hours ALH. Taken together, these data demonstrate that relative levels of Imp and Syp dictate mushroom body neuronal temporal fates (Liu, 2015).

The altered Chinmo protein levels upon Imp or Syp depletion prompted a look at whether Imp and Syp regulate chinmo expression. The abundance of chinmo transcripts normally decreases as neuroblasts age. This pattern was unperturbed in Imp or Syp-depleted neuroblasts. Together, these data suggest that Imp and Syp regulate chinmo expression at a posttranscriptional level (Liu, 2015).

Epistasis was used to explore whether Imp and Syp act to regulate mushroom body neuronal temporal fates through Chinmo. Overexpressing a chinmo transgene partially restored the production of γ neurons by the short-lived, Imp-depleted neuroblasts. Moreover, silencing chinmo transformed the supernumerary γ neurons made by the Syp-depleted neuroblasts into α/β neurons. Together, these observations place Chinmo downstream of Imp and/or Syp in the temporal fate specification of mushroom body (Liu, 2015).

To ascertain whether Imp/Syp gradients serve as a general temporal-fating mechanism, the roles of Imp and Syp were examined in the rapidly changing antennal lobe anterodorsal 1 (ALad1) lineage that yields ~60 larval-born neurons of 22 types. Although all 22 types express acj6-GAL4, only the first 12 types generated express GAL4-GH146. Imp depletion reduced the ALad1 daughter cell number (acj6+) but increased the ratio of late-type to early-type neurons. By contrast, Syp depletion increased total ALad1 daughter cells and increased the percentage of the early-type (GH146+) neurons. Despite precocious production of late-type neurons or prolonged generation of early-type neurons, 21 of the 22 neuron types were preserved. In summary, the opposing Imp/Syp gradients govern temporal fates in at least two different neuroblast lineages that produce mushroom body and antennal lobe neurons functioning in memory and olfaction, respectively (Liu, 2015).

The opposite temporal gradients of Imp and Syp in neuroblasts confer the serially derived daughter cells with graded levels of Imp/Syp. The acquisition of distinct daughter cell fates based on the Imp/Syp morphogens is reminiscent of early embryonic patterning by the opposite spatial gradients of maternally inherited Bicoid and Nanos. Different levels of Bicoid and Nanos are incorporated into cells along the anterior-posterior axis after cellularization of the blastoderm. Bicoid and Nanos function as RNA-binding proteins to initiate anterior-posterior spatial patterning via translational control of maternal transcripts that encode transcription factors. Analogously, temporal fate patterning of newborn neurons is orchestrated by post-transcriptional control of chinmo and potentially other genes by Imp and Syp. Because Imp and Syp may share common targets but show affinity for different RNA motifs, it is possible that Imp and Syp can both bind chinmo transcripts, but they may differentially target chinmo transcripts for translation versus sequestration. Descending Imp temporal gradients governs aging of Drosophila testis stem cell niche. Imp-1, the mammalian ortholog of Imp, is also needed to maintain mouse neural stem cells. It is proposed that graded Imp/Syp expression constitutes an evolutionally conserved mechanism for governing time-dependent stem cell fates, including temporal fate progression in neural stem cells and their derived neuronal lineages (Liu, 2015).

Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity

An important question in neuroscience is how stem cells generate neuronal diversity. During Drosophila embryonic development, neural stem cells (neuroblasts) sequentially express transcription factors that generate neuronal diversity; regulation of the embryonic temporal transcription factor cascade is lineage-intrinsic. In contrast, larval neuroblasts generate longer ~50 division lineages, and currently only one mid-larval molecular transition is known: Chinmo/Imp/Lin-28+ neuroblasts transition to Syncrip+ neuroblasts. This study shows that the hormone ecdysone is required to down-regulate Chinmo/Imp and activate Syncrip, plus two late neuroblast factors, Broad and E93. Seven-up triggers Chinmo/Imp to Syncrip/Broad/E93 transition by inducing expression of the Ecdysone receptor in mid-larval neuroblasts, rendering them competent to respond to the systemic hormone ecdysone. Importantly, late temporal gene expression is essential for proper neuronal and glial cell type specification. This is the first example of hormonal regulation of temporal factor expression in Drosophila embryonic or larval neural progenitors (Syed, 2017).

This study shows that the steroid hormone ecdysone is required to trigger a major gene expression transition at mid-larval stages: central brain neuroblasts transition from Chinmo/Imp to Broad/Syncrip/E93. Furthermore, it was shown that Svp activates expression of EcR-B1 in larval neuroblasts, which gives them competence to respond to ecdysone signaling, thereby triggering this gene expression transition. Although a global reduction of ecdysone levels is likely to have pleiotropic effects on larval development, multiple experiments were performed to show that the absence or delay in late temporal factor expression following reduced ecdysone signaling is not due to general developmental delay. First, the EcR gene itself is expressed at the normal time (~56 hr) in the whole organism ecdysoneless1 mutant, arguing strongly against a general developmental delay. Second, a type II neuroblast seven-up mutant clone shows a complete failure to express EcR and other late factors, in the background of an entirely wild type larvae; this is perhaps the strongest evidence that the phenotypes that are described are not due to a general developmental delay. Third, lineage-specific expression of EcR dominant negative leads to loss of Syncrip and E93 expression without affecting Broad expression; the normal Broad expression argues against a general developmental delay. Fourth, live imaging was used to directly measure cell cycle times, and it was found that lack of ecdysone did not slow neuroblast cell cycle times. Taken together, these data support the conclusion that ecdysone signaling acts directly on larval neuroblasts to promote an early-to-late gene expression transition (Syed, 2017).

The role of ecdysone in regulating developmental transitions during larval stages has been well studied; it can induce activation or repression of suites of genes in a concentration dependent manner. Ecdysone induces these changes through a heteromeric complex of EcR and the retinoid X receptor homolog Ultraspiracle. Ecdysone is required for termination of neuroblast proliferation at the larval/pupal transition, and is known to play a significant role in remodeling of mushroom body neurons and at neuromuscular junctions. This study adds to this list another function: to trigger a major gene expression transition in mid-larval brain neuroblasts (Syed, 2017).

Does ecdysone signaling provide an extrinsic cue that synchronizes larval neuroblast gene expression? Good coordination of late gene expression is not seen, arguing against synchronization. For example, Syncrip can be detected in many neuroblasts by 60 hr, whereas Broad appears slightly later at ~72 hr, and E93 is only detected much later at ~96 hr, by which time Broad is low. This staggered expression of ecdysone target genes is reminiscent of early and late ecdysone-inducible genes in other tissues. In addition, for any particular temporal factor there are always some neuroblasts expressing it prior to others, but not in an obvious pattern. It seems the exact time of expression can vary between neuroblasts. Whether the pattern of response is due to different neuroblast identities, or a stochastic process, remains to be determined (Syed, 2017).

It has been shown preiously that the Hunchback-Krüppel-Pdm-Castor temporal gene transitions within embryonic neuroblasts are regulated by neuroblast-intrinsic mechanisms: they can occur normally in neuroblasts isolated in culture, and the last three factors are sequentially expressed in G2-arrested neuroblasts. Similarly, optic lobe neuroblasts are likely to undergo neuroblast-intrinsic temporal transcription factor transitions, based on the observation that these neuroblasts form over many hours of development and undergo their temporal transitions asynchronously. In contrast, this study shows that ecdysone signaling triggers a mid-larval transition in gene expression in all central brain neuroblasts (both type I and type II). Although ecdysone is present at all larval stages, it triggers central brain gene expression changes only following Svp-dependent expression of EcR-B1 in neuroblasts. Interestingly, precocious expression of EcR-B1 (worniu-gal4 UAS-EcR-B1) did not result in premature activation of the late factor Broad, despite the forced expression of high EcR-B1 levels in young neuroblasts. Perhaps there is another required factor that is also temporally expressed at 56 hr. It is also noted that reduced ecdysone signaling in ecdts mutants or following EcRDN expression does not permanently block the Chinmo/Imp to Broad/Syncrip/E93 transition; it occurs with variable expressivity at 120-160 hr animals (pupariation is significantly delayed in these ecdts mutants), either due to a failure to completely eliminate ecdysone signaling or the presence of an ecdysone-independent mechanism (Syed, 2017).

A small but reproducible difference was found in the effect of reducing ecdysone levels using the biosynthetic pathway mutant ecdts versus expressing a dominant negative EcR in type II neuroblasts. The former genotype shows a highly penetrant failure to activate Broad in old neuroblasts, whereas the latter genotype has normal expression of Broad (despite failure to down-regulate Chinmo/Imp or activate E93). This may be due to failure of the dominant negative protein to properly repress the Broad gene. Differences between EcRDN and other methods of reducing ecdysone signaling have been noted before (Syed, 2017).

Drosophila Svp is an orphan nuclear hormone receptor with an evolutionarily conserved role in promoting a switch between temporal identity factors. In Drosophila, Svp it is required to switch off hunchback expression in embryonic neuroblasts, and in mammals the related COUP-TF1/2 factors are required to terminate early-born cortical neuron production, as well as for the neurogenic to gliogenic switch. This study showed that Svp is required for activating expression of EcR, which drives the mid-larval switch in gene expression from Chinmo/Imp to Syncrip/Broad/E93 in central brain neuroblasts. The results are supported by independent findings that svp mutant clones lack expression of Syncrip and Broad in old type II neuroblasts (Tsumin Lee, personal communication to Chris Doe). Interestingly, Svp is required for neuroblast cell cycle exit at pupal stages, but how the early larval expression of Svp leads to pupal cell cycle exit was a mystery. The current results provide a satisfying link between these findings: Svp was shown to activate expression of EcR-B1, which is required for the expression of multiple late temporal factors in larval neuroblasts. Any one of these factors could terminate neuroblast proliferation at pupal stages, thereby explaining how an early larval factor (Svp) can induce cell cycle exit five days later in pupae. It is interesting that one orphan nuclear hormone receptor (Svp) activates expression of a second nuclear hormone receptor (EcR) in neuroblasts. This motif of nuclear hormone receptors regulating each other is widely used in Drosophila, C. elegans, and vertebrates (Syed, 2017).

The position of the Svp+ neuroblasts varied among the type II neuroblast population from brain-to-brain, suggesting that Svp may be expressed in all type II neuroblasts but in a transient, asynchronous manner. This conclusion is supported by two findings: the svp-lacZ transgene, which encodes a long-lived β-galactosidase protein, can be detected in nearly all type II neuroblasts; and the finding that Svp is required for EcR expression in all type II neuroblasts, consistent with transient Svp expression in all type II neuroblasts. It is unknown what activates Svp in type II neuroblasts; its asynchronous expression is more consistent with a neuroblast-intrinsic cue, perhaps linked to the time of quiescent neuroblast re-activation, than with a lineage-extrinsic cue. It would be interesting to test whether Svp expression in type II neuroblasts can occur normally in isolated neuroblasts cultured in vitro, similar to the embryonic temporal transcription factor cascade (Syed, 2017).

Castor and its vertebrate homolog Cas-Z1 specify temporal identity in Drosophila embryonic neuroblast lineages and vertebrate retinal progenitor lineages, respectively (Mattar, 2015). Although this study shows that Cas is not required for the Chinmo/Imp to Syncrip/Broad/E93 transition, it has other functions. Cas expression in larval neuroblasts is required to establish a temporal Hedgehog gradient that ultimately triggers neuroblast cell cycle exit at pupal stages (Syed, 2017).

Drosophila embryonic neuroblasts change gene expression rapidly, often producing just one progeny in each temporal transcription factor window. In contrast, larval neuroblasts divide ~50 times over their 120 hr lineage. Mushroom body neuroblasts make just four different neuronal classes over time, whereas the AD (ALad1) neuroblast makes ~40 distinct projection neuron subtypes. These neuroblasts probably represent the extremes (one low diversity, suitable for producing Kenyon cells; one high diversity, suitable for generating distinct olfactory projection neurons). This study found that larval type II neuroblasts undergo at least seven molecularly distinct temporal windows. If it is assumed that the graded expression of Imp (high early) and Syncrip (high late) can specify fates in a concentration-dependent manner, many more temporal windows could exist (Syed, 2017).

This study illuminates how the major mid-larval gene expression transition from Chinmo/Imp to Broad/Syncrip/E93 is regulated; yet many new questions have been generated. What activates Svp expression in early larval neuroblasts - intrinsic or extrinsic factors? How do type II neuroblast temporal factors act together with Dichaete, Grainy head, and Eyeless INP temporal factors to specify neuronal identity? Do neuroblast or INP temporal factors activate the expression of a tier of 'morphogenesis transcription factors' similar to leg motor neuron lineages? What are the targets of each temporal factor described here? What types of neurons (or glia) are made during each of the seven distinct temporal factor windows, and are these neurons specified by the factors present at their birth? The identification of new candidate temporal factors in central brain neuroblasts opens up the door for addressing these and other open questions (Syed, 2017).

The asymmetrically segregating lncRNA cherub is required for transforming stem cells into malignant cells

Tumor cells display features that are not found in healthy cells. How they become immortal and how their specific features can be exploited to combat tumorigenesis are key questions in tumor biology.This study describes the long non-coding RNA cherub (long non-coding RNA:CR43283) that is critically required for the development of brain tumors in Drosophila but is dispensable for normal development. In mitotic Drosophila neural stem cells, cherub localizes to the cell periphery and segregates into the differentiating daughter cell. During tumorigenesis, de-differentiation of cherub-high cells leads to the formation of tumorigenic stem cells that accumulate abnormally high cherub levels. cherub establishes a molecular link between the RNA-binding proteins Staufen and Syncrip. As Syncrip is part of the molecular machinery specifying temporal identity in neural stem cells, it is proposed that tumor cells proliferate indefinitely, because cherub accumulation no longer allows them to complete their temporal neurogenesis program (Landskron, 2018).

Throughout the animal kingdom, stem cells supply tissues with specialized cells. They can do this because they have the unique ability to both replicate themselves (an ability termed self-renewal) and to simultaneously generate other daughter cells with a more restricted developmental potential. Besides their role in tissue homeostasis, stem cells have also been linked to tumor formation. They can turn into so-called tumor stem cells that sustain tumor growth indefinitely. The mechanisms that endow tumor stem cells with indefinite proliferation potential are not fully understood (Landskron, 2018).

Most Drosophila brain tumors originate from the so-called type II neuroblasts (NBIIs). NBIIs divide asymmetrically into a larger cell that retains NB characteristics and a smaller intermediate neural progenitor (INP). Newly formed immature INPs (iINPs) go through a defined set of maturation steps to become transit-amplifying mature INPs (mINPs). After this, a mINP undergoes 3-6 divisions generating one mINP and one ganglion mother cell (GMC) that in turn divides into two terminally differentiating neurons or glial cells (Landskron, 2018).

During each NBII division, a set of cell fate determinants is segregated into the INP. Among those are the Notch inhibitor Numb and the TRIM-NHL protein Brain tumor (Brat). Loss of these cell fate determinants leads to the generation of ectopic NB-like cells at the expense of differentiated brain cells. Formation of malignant brain tumors has also been observed upon the depletion of downstream factors that normally maintain the INP fate (Landskron, 2018).

These features make Drosophila a model for the stepwise acquisition of tumor stem cell properties. When numb or brat are inactivated, the smaller NBII progeny fails to establish an INP fate and initially enters a long transient cell cycle arrest. Only after this lag period, the smaller cell regrows to a NB-sized cell that has acquired tumor stem cell properties and that it is therefore refered to as tumor neuroblast (tNB). NBIIs and ectopic tNBs are indistinguishable in terms of markers. Both cell populations are characterized by the expression of self-renewal genes and lack differentiation markers, but nevertheless behave differently. Shortly after entering pupal stages, NBs decrease their cell volumes successively with each NB division before they exit the cell cycle and differentiate. However, tNBs do not shrink during metamorphosis and continue to proliferate even in the adult fly brain. Moreover, in contrast to wild-type brains, the resulting tumor brains can be serially transplanted into host flies for years, indicating the immortality of these tumors (Landskron, 2018).

Similarly, mammalian homologues of numb and brat have been shown to inhibit tumor growth. Furthermore, the human brat homologue TRIM3 is depleted in 24% of gliomas and NUMB protein levels are markedly reduced in 55% of breast tumor cases. Therefore, results obtained in these Drosophila tumor models are highly relevant (Landskron, 2018).

This study used the Drosophila brat tumor model to investigate how tNBs differ from their physiological counterparts, the NBIIs. The results indicate that progression towards a malignant state is an intrinsic process in brat tNBs that does not correlate with stepwise acquisition of DNA alterations. Transcriptome profiling of larval NBs identified the previously uncharacterized long non-coding (lnc) RNA cherub as crucial for tumorigenesis, but largely dispensable for NB development. The data show that cherub is the first identified lncRNA to be asymmetrically segregated during mitosis into INPs, where the initial high cherub levels decrease with time. Upon the loss of brat, the smaller cherub-high cell reverts into an ectopic tNBs resulting in tumors with high cortical cherub. Molecularly, cherub facilitates the binding between the RNA-binding protein Staufen and the late temporal identity factor Syp and consequently tethers Syp to the plasma membrane. Depleting cherub in brat tNBs leads to the release of Syp from the cortex into the cytoplasm and represses tumor growth. These data provide insight into how defects in asymmetric cell division can contribute to the acquisition of tumorigenic traits without the need of DNA alterations (Landskron, 2018).

It is commonly assumed that cancer cells become malignant and gain replicative immortality by acquiring genetic lesions. Surprisingly, however, the current data indicate that brat tumors do not require additional genetic lesions for the transition to an immortal state. This is not a general feature of Drosophila tumors as genomic instability alone can induce tumors in Drosophila epithelial cells and intestinal stem cells. However, the current results are supported by previous experiments demonstrating that defects in genome integrity do not contribute to primary tumor formation in NBs. Similarly, tumors induced by loss of epigenetic regulators in Drosophila wing discs do not display genome instability. In addition, the short time it takes from the inactivation of brat to the formation of a fully penetrant tumor phenotype would most likely be insufficient for the acquisition of tumor-promoting DNA alterations. More likely, the enormous self-renewal capacity and fast cell cycle of Drosophila NBs requires only minor alterations for the adoption of malignant growth. Interestingly, epigenetic tumorigenesis has been described before in humans, where childhood brain tumors only harbor an extremely low mutation rate and very few recurrent DNA alterations. Comparable observations have been made for leukemia. The current results might help to understand mechanisms of epigenetic tumor formation, which are currently unclear in humans (Landskron, 2018).

cherub is the first lncRNA described to segregate asymmetrically during mitosis. Once cherub is allocated through binding to the RNA-binding protein Staufen into the cytoplasm of INPs, its levels decrease over time. The results show that the inability to segregate cherub into differentiating cells leads to its accumulation in tNBs. The increasing amount of tumor transcriptome data indicates that a vast number of lncRNAs show increased expression levels in various tumor types. Intriguingly, the mammalian homologue of cherub's binding partner Staufen has been also described to asymmetrically localize RNA in dividing neural stem cells. Hence, besides transcriptional upregulation, asymmetric distribution of lncRNAs between sibling cells might play a role in the accumulation of such RNAs in mammalian tumors (Landskron, 2018).

The data suggest a functional connection between cherub and proteins involved in temporal neural stem cell patterning. This study that tNBs retain the early temporal identity factor Imp even during late larval stages. However, IGF-II mRNA-binding protein (Imp) expression in brat mutants is heterogeneous and only a subpopulation of tNBs maintains young identity (Landskron, 2018).

Tumor heterogeneity has also been described for pros tumors, where only a subset of tNBs maintains expression of the early temporal factors Imp and Chinmo. Interestingly, it is this subpopulation that drives tumor growth in prospero tumors (Landskron, 2018).

Consistent with this, genetic experiments show that 'rejuvenating' tNBs enhances tumor growth and consequently increases the survival of tumor bearing flies, whereas 'aging' tNBs identity has the opposite effect. Although mammalian counterparts of Imp have not yet being shown to act as temporal identity genes, their upregulated expression has been implied in various cancer types. Therefore, temporal patterning of NBs has an essential role in brain tumor propagation in Drosophila (Landskron, 2018).

The subset of tNBs that retain early identity in tumors is lost in a cherub mutant background. This suggests that cherub itself might regulate temporal identity. In NBs and tNBs cherub regulates Syp localization by facilitating the binding of Syp to Staufen and thus recruiting it to the cell cortex. In tumors depleted of cherub, Syp localizes mainly to the cytoplasm and is no longer observed at the cortex. As the removal of Syp in tNBs leads to enhanced tumor growth and early lethality, those data suggest that cherub could control temporal NB identity by regulating the subcellular localization of Syp(Landskron, 2018).

How could cherub regulate the function of Syp? The RNA-binding protein Syp is a translational regulator and has been suggested to control mRNA stability. As mammalian SYNCRIP/hnRNP Q interacts with a lncRNA that suppresses translation, cherub might regulate Syp to inhibit or promote the translation of a subset of target mRNAs. In particular, in NBs Syp acts at two stages in NBs during development: Firstly, approximately 60 hr after larval hatching it represses early temporal NB factors, like Imp. Secondly, at the end of the NB lifespan Syp promotes levels of the differentiation factor prospero to facilitate the NB's final cell cycle exit. As cherub depletion in brat tumors leads to decreased tumor growth, it is possible that cherub inhibits the Syp-dependent repression of the early factor Imp, which this study shows to be required for optimal tumor growth. However, cherub mutant NBIIs do not show altered timing or expression of Imp during development. In accordance, brat tumors show high cortical cherub levels, but only a subset of NBs expresses Imp. Rather than rendering Syp completely inactive, it is suggested that cherub decreases the ability of Syp to promote factors important to restrict NB proliferation. As prospero is not expressed in NBIIs, it remains to be investigated which Syp targets are affected by cherub (Landskron, 2018).

Remarkably, cherub mutants are viable, fertile and do not affect NBII lineages. Neurons generated by NBIIs predominantly integrate into the adult brain structure termed central complex, which is important for locomotor activity. As cherub mutants show normal geotaxis, function of the lncRNA seems dispensable for NBIIs to generate their neural descendants (Landskron, 2018).

Nevertheless, the conserved secondary RNA structures of cherub and its conserved expression pattern in other Drosophila species suggest that it has a functional role. There are several possibilities why no phenotype is observed upon the loss of cherub. In wild-type flies cherub might confer robustness. A similar scenario was observed in embryonic NBs, in which Staufen segregates prospero mRNA into GMCs. The failure to segregate prospero mRNA does not result in a phenotype, but it enhances the hypomorphic prospero GMC phenotype. Thus segregation of prospero mRNA serves as support for Prospero protein to induce a GMC fate. Similarly, cherub could act as a backup to reliably establish correct Syp levels in NBIIs and in INPs. Alternatively, cherub might fine-tune the temporal patterning by regulating the cytoplasmic pool of Syp in the NBs. Increasing Syp levels have been suggested to determine distinct temporal windows, in which different INPs and ultimately neurons with various morphologies are sequentially born. Therefore, it cannot be excluded that changes in Syp levels lead to subtle alterations in the number of certain neuron classes produced by NBIIs that only reveal themselves in pathological conditions like tumorigenesis (Landskron, 2018).

This study illustrates how a lncRNA can control the subcellular localization of temporal factors. In addition to temporal NB identity, Syp regulates synaptic transmission and maternal RNA localization. While cherub is not expressed in ovaries or adult heads, Staufen has been implicated in these processes, suggesting that other RNAs might act similarly to cherub. Interestingly, the mammalian Syp homolog hnRNP Q binds the noncoding RNA BC200, whose upregulation is used as a biomarker in ovarian, esophageal, breast and brain cancer. In the future, it will be interesting to investigate whether the mechanism identified in Drosophila is involved in mammalian tumorigenesis as well (Landskron, 2018).

Drosophila Syncrip binds the gurken mRNA localisation signal and regulates localised transcripts during axis specification

In the Drosophila oocyte, mRNA transport and localised translation play a fundamental role in axis determination and germline formation of the future embryo. gurken mRNA encodes a secreted TGF-alpha signal that specifies dorsal structures, and is localised to the dorso-anterior corner of the oocyte via a cis-acting 64 nucleotide gurken localisation signal. Using GRNA chromatography, this study characterised the biochemical composition of the ribonucleoprotein complexes that form around the gurken mRNA localisation signal in the oocyte. A number of the factors already known to be involved in gurken localisation and translational regulation, such as Squid and Imp, were identified, in addition to a number of factors with known links to mRNA localisation, such as Me31B and Exu. Previously uncharacterised Drosophila proteins were identified, including the fly homologue of mammalian SYNCRIP/hnRNPQ, a component of RNA transport granules in the dendrites of mammalian hippocampal neurons. It was shown that Drosophila Syncrip binds specifically to gurken and oskar, but not bicoid transcripts. The loss-of-function and overexpression phenotypes of syncrip in Drosophila egg chambers show that the protein is required for correct grk and osk mRNA localisation and translational regulation. It is concluded that Drosophila Syncrip is a new factor required for localisation and translational regulation of oskar and gurken mRNA in the oocyte. It is proposed that Syncrip/SYNCRIP is part of a conserved complex associated with localised transcripts and required for their correct translational regulation in flies and mammals (McDermott, 2012).

This study has identified Drosophila Syp as a novel conserved component of localised RNP granules. Syp associates specifically with grk and osk and is required for their localisation and translational regulation in the Drosophila germline. Although SYNCRIP has been studied in mammalian cells using biochemical approaches, this study is the first to address the function of Syp in vivo, and particularly in generating cellular asymmetry in the germline. Despite a number of genetic screens that have been carried out to identify the genes required for axis specification in flies, Syp was not previously identified as being required for axis determination. This work together with a number of other biochemical based studies illustrates that there are many other essential factors that are still to be identified as having a role in axis specification (McDermott, 2012).

Evidence is presented in this study that Syp is required for axis specification and germline formation by affecting the localisation and translation of grk and osk mRNAs. The phenotypes of loss of function mutations in the gene, and overexpression of the protein support an interesting role for Syp in regulating grk and osk mRNAs. It is noted that the loss of function phenotypes are of low penetrance and are such that further studies are required to uncover the precise mechanism of Syp function. However, Syp is not the only component of grk and osk mRNPs that has a partially penetrant loss of function phenotype. Indeed, others such as IGF-II mRNA-binding protein (Imp) give a stronger phenotype only when in combination with other mutations. Unexpectedly, overexpression of Syp gives the same phenotype as its loss of function, but at a higher penetrance. These results are potentially interesting, but difficult to interpret with certainty. The interpretation is favoured that a certain stoichiometry is necessary within the RNP complexes in which Syp is found. Overexpression of Syp may cause the displacement of certain translational repressors, allowing grk mRNA to be prematurely translated in the nurse cells. In contrast, with loss of function of Syp, grk mRNA localisation and translational regulation may be disrupted in different ways because loss of Syp could lead to decreased stability of the RNP complex. This could in turn lead to the loss of certain components necessary for localization and translational regulation. The eggshell phenotypes observed in the syp germline clones also include some defects that are not typical of a disruption of grk mRNA localisation and translation. These results are interpreted as indicating that Syp has additional target mRNAs in the germline whose localisation and/or translation are affected in the syp mutant. On the basis of the morphological defects observed in a number of eggs these targets may include mRNAs involved in follicle cell migration or actin organisation during oogenesis, such as bullwinkle (bwk) or chickadee (chic). Mislocalisation and/or altered translation of these mRNAs could result in the shorter eggs and the bwk-like dorsal appendage defects that are observed (McDermott, 2012).

The physical association of Syp with these mRNAs further supports a function for Syp in the regulation of grk and osk mRNAs, although it is unclear whether this is through a direct or indirect interaction. Syp does not appear to colocalise with localised grk or osk in the oocyte, and so Syp may function before the mRNAs reach their final destination in the oocyte in order to influence localisation and translation. Syp was also identified biochemically with a number of the factors already known to be required for grk and osk mRNA localisation and translational regulation. These include Sqd, Imp, PTB, PABP, Me31B and BicC. The homologues of these factors were also identified in biochemical studies of SYNCRIP interactors in mammalian cells. Therefore, it is proposed that the current results have uncovered a conserved module of RNA binding proteins that are required for both mRNA transport and translational regulation. The Syp associated complex that this study has uncovered binds to grk via a relatively small stem loop sequence, the GLS. While Syp also associates with osk mRNA, the minimal region necessary and sufficient for osk mRNA localisation has not yet been defined. Therefore, it is unknown whether a small region is required in this case, and if so whether it is in any way similar to the GLS, structurally or in primary sequence (McDermott, 2012).

Taking the results of this study in the context of other data and the previous publications on SYNCRIP and its associated proteins in mammalian hippocampal neurons, it is proposed that Syp may be present at neuronal synapses in a complex with at least some of the same proteins that are required for grk mRNA localisation. This idea is supported by the fact that at least some of these factors, namely Sqd, Imp, PTB, PABP and Me31B are also present in the Drosophila nervous system. The expression studies show that Syp is absent from embryos but is highly expressed in the larval nervous system. Given the role of Syp in mRNA localization and translational regulation in the oocyte, and its presence in larval brains, it is proposed that Syp could have a similar function in the nervous system. In comparison with the oocyte, much less is known about localised transcripts and their translational regulation in the nervous system, and it remains to be determined to what extent this proposal is valid and in which neuronal tissues Syp is required in larvae. Nevertheless, this work is the first demonstration that Syp functions in mRNA localisation and translational control in the oocyte and coupled with the work on mammalian SYNCRIP showing association with RNP granules in the dendrites of hippocampal neurons it is attractive to propose that Syp protein also has a conserved function in regulation of neuronal mRNAs (McDermott, 2012).

Functions of Syncrip orthologs in other species

Control of translation and miRNA-dependent repression by a novel poly(A) binding protein, hnRNP-Q

Translation control often operates via remodeling of messenger ribonucleoprotein particles. The poly(A) binding protein (PABP) simultaneously interacts with the 3' poly(A) tail of the mRNA and the eukaryotic translation initiation factor 4G (eIF4G) to stimulate translation. PABP also promotes miRNA-dependent deadenylation and translational repression of target mRNAs. This study demonstrates that isoform 2 of the mouse heterogeneous nuclear protein Q (hnRNP-Q2/SYNCRIP) binds poly(A) by default when PABP binding is inhibited. In addition, hnRNP-Q2 competes with PABP for binding to poly(A) in vitro. Depleting hnRNP-Q2 from translation extracts stimulates cap-dependent and IRES-mediated translation that is dependent on the PABP/poly(A) complex. Adding recombinant hnRNP-Q2 to the extracts inhibits translation in a poly(A) tail-dependent manner. The displacement of PABP from the poly(A) tail by hnRNP-Q2 impairs the association of eIF4E with the 5' m(7)G cap structure of mRNA, resulting in the inhibition of 48S and 80S ribosome initiation complex formation. In mouse fibroblasts, silencing of hnRNP-Q2 stimulates translation. In addition, hnRNP-Q2 impedes let-7a miRNA-mediated deadenylation and repression of target mRNAs, which require PABP. Thus, by competing with PABP, hnRNP-Q2 plays important roles in the regulation of global translation and miRNA-mediated repression of specific mRNAs (Svitkin, 2013).

Negative regulation of RhoA translation and signaling by hnRNP-Q1 affects cellular morphogenesis

The small GTPase RhoA has critical functions in regulating actin dynamics affecting cellular morphogenesis through the RhoA/Rho kinase (ROCK) signaling cascade. RhoA signaling controls stress fiber and focal adhesion formation and cell motility in fibroblasts. RhoA signaling is involved in several aspects of neuronal development, including neuronal migration, growth cone collapse, dendrite branching, and spine growth. Altered RhoA signaling is implicated in cancer and neurodegenerative disease and is linked to inherited intellectual disabilities. Although much is known about factors regulating RhoA activity and/or degradation, little is known about molecular mechanisms regulating RhoA expression and the subsequent effects on RhoA signaling. It was hypothesized that posttranscriptional control of RhoA expression may provide a mechanism to regulate RhoA signaling and downstream effects on cell morphology. This study uncover a cellular function for the mRNA-binding protein heterogeneous nuclear ribonucleoprotein (hnRNP) Q1 in the control of dendritic development and focal adhesion formation that involves the negative regulation of RhoA synthesis and signaling. hnRNP-Q1 represses RhoA translation and knockdown of hnRNP-Q1 induces phenotypes associated with elevated RhoA protein levels and RhoA/ROCK signaling. These morphological changes were rescued by ROCK inhibition and/or RhoA knockdown. These findings further suggest that negative modulation of RhoA mRNA translation can provide control over downstream signaling and cellular morphogenesis (Xing, 2012).

hnRNP Q regulates Cdc42-mediated neuronal morphogenesis

The RNA-binding protein hnRNP Q has been implicated in neuronal mRNA metabolism. This study shows that knockdown of hnRNP Q increased neurite complexity in cultured rat cortical neurons and induced filopodium formation in mouse neuroblastoma cells. Reexpression of hnRNP Q1 in hnRNP Q-depleted cells abrogated the morphological changes of neurites, indicating a specific role for hnRNP Q1 in neuronal morphogenesis. A search for mRNA targets of hnRNP Q1 identified functionally coherent sets of mRNAs encoding factors involved in cellular signaling or cytoskeletal regulation and determined its preferred binding sequences. hnRNP Q1 binds to a set of identified mRNAs encoding the components of the actin nucleation-promoting Cdc42/N-WASP/Arp2/3 complex and in part colocalizes with Cdc42 mRNA in granules. Using subcellular fractionation and immunofluorescence, this study showed that knockdown of hnRNP Q reduced the level of some of those mRNAs in neurites and redistributed their encoded proteins from neurite tips to soma to different extents. Overexpression of dominant negative mutants of Cdc42 or N-WASP compromised hnRNP Q depletion-induced neurite complexity. Together, these results suggest that hnRNP Q1 may participate in localization of mRNAs encoding Cdc42 signaling factors in neurites, and thereby may regulate actin dynamics and control neuronal morphogenesis (Chen, 2012).

Rhythmic interaction between Period1 mRNA and hnRNP Q leads to circadian time-dependent translation
The mouse PERIOD1 (mPER1) protein, along with other clock proteins, plays a crucial role in the maintenance of circadian rhythms. mPER1 also provides an important link between the circadian system and the cell cycle system. This study shows that the circadian expression of mPER1 is regulated by rhythmic translational control of mPer1 mRNA together with transcriptional modulation. This time-dependent translation is controlled by an internal ribosomal entry site (IRES) element in the 5' untranslated region (5'-UTR) of mPer1 mRNA along with the trans-acting factor mouse heterogeneous nuclear ribonucleoprotein Q (mhnRNP Q). Knockdown of mhnRNP Q causes a decrease in mPER1 levels and a slight delay in mPER1 expression without changing mRNA levels. The rate of IRES-mediated translation exhibits phase-dependent characteristics through rhythmic interactions between mPer1 mRNA and mhnRNP Q. This study demonstrates 5'-UTR-mediated rhythmic mPer1 translation and provides evidence for posttranscriptional regulation of the circadian rhythmicity of core clock genes (Lee, 2012).

An RNA-interacting protein, SYNCRIP (heterogeneous nuclear ribonuclear protein Q1/NSAP1) is a component of mRNA granule transported with inositol 1,4,5-trisphosphate receptor type 1 mRNA in neuronal dendrites

mRNA transport and local translation in the neuronal dendrite is implicated in the induction of synaptic plasticity. An RNA-interacting protein, SYNCRIP (heterogeneous nuclear ribonuclear protein Q1/NSAP1), is suggested to be important for the stabilization of mRNA. This study reports that SYNCRIP is a component of mRNA granules in rat hippocampal neurons. SYNCRIP was mainly found at cell bodies, but punctate expression patterns in the proximal dendrite were also seen. Time-lapse analysis in living neurons revealed that the granules labeled with fluorescent protein-tagged SYNCRIP were transported bi-directionally within the dendrite at approximately 0.05 microm/s. Treatment of neurons with nocodazole significantly inhibits the movement of green fluorescent protein-SYNCRIP-positive granules, indicating that the transport of SYNCRIP-containing granules is dependent on microtubules. The distribution of SYNCRIP-containing granules overlaps with that of dendritic RNAs and elongation factor 1alpha. SYNCRIP is also found to be co-transported with green fluorescent protein-tagged human staufen1 and the 3'-untranslated region of inositol 1,4,5-trisphosphate receptor type 1 mRNA. These results suggest that SYNCRIP is transported within the dendrite as a component of mRNA granules and raise the possibility that mRNA turnover in mRNA granules and the regulation of local protein synthesis in neuronal dendrites may involve SYNCRIP (Bannai, 2004).

Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?

Spinal muscular atrophy (SMA), the most common hereditary motor neuron disease in children and young adults is caused by mutations in the telomeric survival motor neuron (SMN1) gene. The human genome, in contrast to mouse, contains a second SMN gene (SMN2) which codes for a gene product which is alternatively spliced at the C-terminus, but also gives rise to low levels of full-length SMN protein. The reason why reduced levels of the ubiquitously expressed SMN protein lead to specific motor neuron degeneration without affecting other cell types is still not understood. Using yeast two-hybrid techniques, hnRNP-R and the highly related gry-rbp/hnRNP-Q were identified as novel SMN interaction partners. These proteins have previously been identified in the context of RNA processing, in particular mRNA editing, transport and splicing. hnRNP-R and gry-rbp/hnRNP-Q interact with wild-type Smn but not with truncated or mutant Smn forms identified in SMA. Both proteins are widely expressed and developmentally regulated with expression peaking at E19 in mouse spinal cord. hnRNP-R binds RNA through its RNA recognition motif domains. Interestingly, hnRNP-R is predominantly located in axons of motor neurons and co-localizes with Smn in this cellular compartment. Thus, this finding could provide a key to understand a motor neuron-specific Smn function in SMA (Rossoll, 2002).


Search PubMed for articles about Drosophila Syncrip

Bannai, H., Fukatsu, K., Mizutani, A., Natsume, T., Iemura, S., Ikegami, T., Inoue, T. and Mikoshiba, K. (2004). An RNA-interacting protein, SYNCRIP (heterogeneous nuclear ribonuclear protein Q1/NSAP1) is a component of mRNA granule transported with inositol 1,4,5-trisphosphate receptor type 1 mRNA in neuronal dendrites. J Biol Chem 279: 53427-53434. PubMed ID: 15475564

Chen, H. H., Chang, J. G., Lu, R. M., Peng, T. Y. and Tarn, W. Y. (2008). The RNA binding protein hnRNP Q modulates the utilization of exon 7 in the survival motor neuron 2 (SMN2) gene. Mol Cell Biol 28: 6929-6938. PubMed ID: 18794368

Chen, H. H., Yu, H. I., Chiang, W. C., Lin, Y. D., Shia, B. C. and Tarn, W. Y. (2012). hnRNP Q regulates Cdc42-mediated neuronal morphogenesis. Mol Cell Biol 32: 2224-2238. PubMed ID: 22493061

Duning, K., Buck, F., Barnekow, A. and Kremerskothen, J. (2008). SYNCRIP, a component of dendritically localized mRNPs, binds to the translation regulator BC200 RNA. J Neurochem 105: 351-359. PubMed ID: 18045242

Elvira, G., Wasiak, S., Blandford, V., Tong, X. K., Serrano, A., Fan, X., del Rayo Sanchez-Carbente, M., Servant, F., Bell, A. W., Boismenu, D., Lacaille, J. C., McPherson, P. S., DesGroseillers, L. and Sossin, W. S. (2006). Characterization of an RNA granule from developing brain. Mol Cell Proteomics 5: 635-651. PubMed ID: 16352523

Halstead, J. M., Lin, Y. Q., Durraine, L., Hamilton, R. S., Ball, G., Neely, G. G., Bellen, H. J. and Davis, I. (2014). Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse. Biol Open. PubMed ID: 25171887

Kanai, Y., Dohmae, N. and Hirokawa, N. (2004). Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43: 513-525. PubMed ID: 15312650

Landskron, L., Steinmann, V., Bonnay, F., Burkard, T. R., Steinmann, J., Reichardt, I., Harzer, H., Laurenson, A. S., Reichert, H. and Knoblich, J. A. (2018). The asymmetrically segregating lncRNA cherub is required for transforming stem cells into malignant cells. Elife 7. PubMed ID: 29580384

Lee, K. H., Woo, K. C., Kim, D. Y., Kim, T. D., Shin, J., Park, S. M., Jang, S. K. and Kim, K. T. (2012). Rhythmic interaction between Period1 mRNA and hnRNP Q leads to circadian time-dependent translation. Mol Cell Biol 32: 717-728. PubMed ID: 22124155

Liu, Z., Yang, C. P., Sugino, K., Fu, C. C., Liu, L. Y., Yao, X., Lee, L. P. and Lee, T. (2015). Opposing intrinsic temporal gradients guide neural stem cell production of varied neuronal fates. Science 350: 317-320. PubMed ID: 26472907

McDermott, S. M., Meignin, C., Rappsilber, J. and Davis, I. (2012). Drosophila Syncrip binds the gurken mRNA localisation signal and regulates localised transcripts during axis specification. Biol Open 1: 488-497. PubMed ID: 23213441

McDermott, S. M., Yang, L., Halstead, J. M., Hamilton, R. S., Meignin, C. and Davis, I. (2014). Drosophila Syncrip modulates the expression of mRNAs encoding key synaptic proteins required for morphology at the neuromuscular junction. RNA 20(10): 1593-606. PubMed ID: 25171822

Mizutani, A., Fukuda, M., Ibata, K., Shiraishi, Y. and Mikoshiba, K. (2000). SYNCRIP, a cytoplasmic counterpart of heterogeneous nuclear ribonucleoprotein R, interacts with ubiquitous synaptotagmin isoforms. J Biol Chem 275: 9823-9831. PubMed ID: 10734137

Munro, T. P., Kwon, S., Schnapp, B. J. and St Johnston, D. (2006). A repeated IMP-binding motif controls oskar mRNA translation and anchoring independently of Drosophila melanogaster IMP. J Cell Biol 172: 577-588. PubMed ID: 16476777

Puckelwartz, M. J., Kessler, E., Zhang, Y., Hodzic, D., Randles, K. N., Morris, G., Earley, J. U., Hadhazy, M., Holaska, J. M., Mewborn, S. K., Pytel, P. and McNally, E. M. (2009). Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice. Hum Mol Genet 18: 607-620. PubMed ID: 19008300

Puckelwartz, M. J., Kessler, E. J., Kim, G., Dewitt, M. M., Zhang, Y., Earley, J. U., Depreux, F. F., Holaska, J., Mewborn, S. K., Pytel, P. and McNally, E. M. (2010). Nesprin-1 mutations in human and murine cardiomyopathy. J Mol Cell Cardiol 48: 600-608. PubMed ID: 19944109

Rossoll, W., Kroning, A. K., Ohndorf, U. M., Steegborn, C., Jablonka, S. and Sendtner, M. (2002). Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons? Hum Mol Genet 11: 93-105. PubMed ID: 11773003

Sen, A., Dimlich, D. N., Guruharsha, K. G., Kankel, M. W., Hori, K., Yokokura, T., Brachat, S., Richardson, D., Loureiro, J., Sivasankaran, R., Curtis, D., Davidow, L. S., Rubin, L. L., Hart, A. C., Van Vactor, D. and Artavanis-Tsakonas, S. (2013). Genetic circuitry of Survival motor neuron, the gene underlying spinal muscular atrophy. Proc Natl Acad Sci U S A 110: E2371-2380. PubMed ID: 23757500

Syed, M. H., Mark, B. and Doe, C. Q. (2017). Steroid hormone induction of temporal gene expression in Drosophila brain neuroblasts generates neuronal and glial diversity. Elife 6 [Epub ahead of print]. PubMed ID: 28394252

Van De Bor, V., Hartswood, E., Jones, C., Finnegan, D. and Davis, I. (2005). gurken and the I factor retrotransposon RNAs share common localization signals and machinery. Dev Cell 9: 51-62. PubMed ID: 15992540

Xing, L., Yao, X., Williams, K. R. and Bassell, G. J. (2012). Negative regulation of RhoA translation and signaling by hnRNP-Q1 affects cellular morphogenesis. Mol Biol Cell 23: 1500-1509. PubMed ID: 22357624

Biological Overview

date revised: 13 August 2018

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