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ISSUE HIGHLIGHTS [Issue Highlights]

January 29, 2018 - 9:17am
Categories: Genetics News Feed

Protecting and Diversifying the Germline [Stem Cells and Germlines]

January 29, 2018 - 9:17am

Gametogenesis represents the most dramatic cellular differentiation pathways in both female and male flies. At the genome level, meiosis ensures that diploid germ cells become haploid gametes. At the epigenome level, extensive changes are required to turn on and shut off gene expression in a precise spatiotemporally controlled manner. Research applying conventional molecular genetics and cell biology, in combination with rapidly advancing genomic tools have helped us to investigate (1) how germ cells maintain lineage specificity throughout their adult reproductive lifetime; (2) what molecular mechanisms ensure proper oogenesis and spermatogenesis, as well as protect genome integrity of the germline; (3) how signaling pathways contribute to germline-soma communication; and (4) if such communication is important. In this chapter, we highlight recent discoveries that have improved our understanding of these questions. On the other hand, restarting a new life cycle upon fertilization is a unique challenge faced by gametes, raising questions that involve intergenerational and transgenerational epigenetic inheritance. Therefore, we also discuss new developments that link changes during gametogenesis to early embryonic development—a rapidly growing field that promises to bring more understanding to some fundamental questions regarding metazoan development.

Categories: Genetics News Feed

Mosaic Analysis in Drosophila [Methods]

January 29, 2018 - 9:17am

Since the founding of Drosophila genetics by Thomas Hunt Morgan and his colleagues over 100 years ago, the experimental induction of mosaicism has featured prominently in its recognition as an unsurpassed genetic model organism. The use of genetic mosaics has facilitated the discovery of a wide variety of developmental processes, identified specific cell lineages, allowed the study of recessive embryonic lethal mutations, and demonstrated the existence of cell competition. Here, we discuss how genetic mosaicism in Drosophila became an invaluable research tool that revolutionized developmental biology. We describe the prevailing methods used to produce mosaic animals, and highlight advantages and disadvantages of each genetic system. We cover methods ranging from simple "twin-spot" analysis to more sophisticated systems of multicolor labeling.

Categories: Genetics News Feed

Repressive Chromatin in Caenorhabditis elegans: Establishment, Composition, and Function [Gene and Genome Regulatory Mechanisms]

January 29, 2018 - 9:17am

Chromatin is organized and compacted in the nucleus through the association of histones and other proteins, which together control genomic activity. Two broad types of chromatin can be distinguished: euchromatin, which is generally transcriptionally active, and heterochromatin, which is repressed. Here we examine the current state of our understanding of repressed chromatin in Caenorhabditis elegans, focusing on roles of histone modifications associated with repression, such as methylation of histone H3 lysine 9 (H3K9me2/3) or the Polycomb Repressive Complex 2 (MES-2/3/6)-deposited modification H3K27me3, and on proteins that recognize these modifications. Proteins involved in chromatin repression are important for development, and have demonstrated roles in nuclear organization, repetitive element silencing, genome integrity, and the regulation of euchromatin. Additionally, chromatin factors participate in repression with small RNA pathways. Recent findings shed light on heterochromatin function and regulation in C. elegans, and should inform our understanding of repressed chromatin in other animals.

Categories: Genetics News Feed

Comparative Oligo-FISH Mapping: An Efficient and Powerful Methodology To Reveal Karyotypic and Chromosomal Evolution [Methods, Technology, and Resources]

January 29, 2018 - 9:17am

Developing the karyotype of a eukaryotic species relies on identification of individual chromosomes, which has been a major challenge for most nonmodel plant and animal species. We developed a novel chromosome identification system by selecting and labeling oligonucleotides (oligos) located in specific regions on every chromosome. We selected a set of 54,672 oligos (45 nt) based on single copy DNA sequences in the potato genome. These oligos generated 26 distinct FISH signals that can be used as a "bar code" or "banding pattern" to uniquely label each of the 12 chromosomes from both diploid and polyploid (4x and 6x) potato species. Remarkably, the same bar code can be used to identify the 12 homeologous chromosomes among distantly related Solanum species, including tomato and eggplant. Accurate karyotypes based on individually identified chromosomes were established in six Solanum species that have diverged for >15 MY. These six species have maintained a similar karyotype; however, modifications to the FISH signal bar code led to the discovery of two reciprocal chromosomal translocations in Solanum etuberosum and S. caripense. We also validated these translocations by oligo-based chromosome painting. We demonstrate that the oligo-based FISH techniques are powerful new tools for chromosome identification and karyotyping research, especially for nonmodel plant species.

Categories: Genetics News Feed

Detection of Epistasis for Flowering Time Using Bayesian Multilocus Estimation in a Barley MAGIC Population [Multiparental Populations]

January 29, 2018 - 9:17am

Gene-by-gene interactions, also known as epistasis, regulate many complex traits in different species. With the availability of low-cost genotyping it is now possible to study epistasis on a genome-wide scale. However, identifying genome-wide epistasis is a high-dimensional multiple regression problem and needs the application of dimensionality reduction techniques. Flowering Time (FT) in crops is a complex trait that is known to be influenced by many interacting genes and pathways in various crops. In this study, we successfully apply Sure Independence Screening (SIS) for dimensionality reduction to identify two-way and three-way epistasis for the FT trait in a Multiparent Advanced Generation Inter-Cross (MAGIC) barley population using the Bayesian multilocus model. The MAGIC barley population was generated from intercrossing among eight parental lines and thus, offered greater genetic diversity to detect higher-order epistatic interactions. Our results suggest that SIS is an efficient dimensionality reduction approach to detect high-order interactions in a Bayesian multilocus model. We also observe that many of our findings (genomic regions with main or higher-order epistatic effects) overlap with known candidate genes that have been already reported in barley and closely related species for the FT trait.

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Mild Telomere Dysfunction as a Force for Altering the Adaptive Potential of Subtelomeric Genes [Genome Integrity and Transmission]

January 29, 2018 - 9:17am

Subtelomeric regions have several unusual characteristics, including complex repetitive structures, increased rates of evolution, and enrichment for genes involved in niche adaptation. The adaptive telomere failure hypothesis suggests that certain environmental stresses can induce a low level of telomere failure, potentially leading to elevated subtelomeric recombination that could result in adaptive mutational changes within subtelomeric genes. Here, we tested a key prediction of the adaptive telomere failure hypothesis—that telomere dysfunction mild enough to have little or no overall effect on cell fitness could still lead to substantial increases in the mutation rates of subtelomeric genes. Our results show that a mutant of Kluyveromyces lactis with stably short telomeres produced a large increase in the frequency of mutations affecting the native subtelomeric β-galactosidase (LAC4) gene. All lac4 mutants examined from strains with severe telomere dysfunction underwent terminal deletion/duplication events consistent with being due to break-induced replication. In contrast, although cells with mild telomere dysfunction also exhibited similar terminal deletion and duplication events, up to 50% of lac4 mutants from this background unexpectedly contained base changes within the LAC4 coding region. This mutational bias for producing base changes demonstrates that mild telomere dysfunction can be well suited as a force for altering the adaptive potential of subtelomeric genes.

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The Germline-Specific Factor OEF-1 Facilitates Coordinated Progression Through Germ Cell Development in Caenorhabditis elegans [Genome Integrity and Transmission]

January 29, 2018 - 9:17am

The purpose of germ cells is to ensure the faithful transmission of genetic material to the next generation. To develop into mature gametes, germ cells must pass through cell cycle checkpoints while maintaining totipotency and genomic integrity. How germ cells coordinate developmental events while simultaneously protecting their unique fate is not well understood. Here, we characterize a novel nuclear protein, Oocyte-Excluded Factor-1 (OEF-1), with highly specific germline expression in Caenorhabditis elegans. OEF-1 is initially detected early in embryogenesis and is expressed in the nuclei of all germ cells during larval stages. In adults, OEF-1 expression abruptly decreases just prior to oocyte differentiation. In oef-1 mutants, the developmental progression of germ cells is accelerated, resulting in subtle defects at multiple stages of germ cell development. Lastly, OEF-1 is primarily associated with the bodies of germline-expressed genes, and as such is excluded from the X chromosome. We hypothesize that OEF-1 may regulate the rate of progression through germ cell development, providing insight into how these critical maturation events are coordinated.

Categories: Genetics News Feed

A Failsafe for Sensing Chromatid Tension in Mitosis with the Histone H3 Tail in Saccharomyces cerevisiae [Genome Integrity and Transmission]

January 29, 2018 - 9:17am

Mitotic fidelity is ensured by achieving biorientation on all paired chromosomes. The key signal for proper chromosome alignment is the tension between sister chromatids created by opposing poleward force from the spindles. In the budding yeast, the tension-sensing function requires that the Shugoshin protein, Shugoshin 1, be recruited to the centromeres and the neighboring pericentric regions. Concerted actions integrating proteins at centromeres and pericentromeres create highly specific Shugoshin 1 domains on mitotic chromosomes. We have previously reported that an important regulatory region on histone H3, termed the tension-sensing motif (TSM), is responsible for retaining Shugoshin 1 at pericentromeres. The TSM is negatively regulated by the acetyltransferase Gcn5p, but the underlying mechanism was elusive. In this work, we provide evidence that, when the TSM function is impaired, the histone H3 tail adopts a role that complements the damaged TSM to ensure faithful mitosis. This novel function of the H3 tail is controlled by Gcn5p, which targets selective lysine residues. Mutations to K14 and K23 ameliorate the mitotic defects resulting from TSM mutations. The restoration of faithful segregation is accompanied by regaining Shugoshin 1 access to the pericentric regions. Our data reveal a novel pathway for mitotic Shugoshin 1 recruitment and further reinforce the active role played by chromatins during their segregation in mitosis.

Categories: Genetics News Feed

Loss of Drosophila Mei-41/ATR Alters Meiotic Crossover Patterning [Genome Integrity and Transmission]

January 29, 2018 - 9:17am

Meiotic crossovers must be properly patterned to ensure accurate disjunction of homologous chromosomes during meiosis I. Disruption of the spatial distribution of crossovers can lead to nondisjunction, aneuploidy, gamete dysfunction, miscarriage, or birth defects. One of the earliest identified genes involved in proper crossover patterning is Drosophila mei-41, which encodes the ortholog of the checkpoint kinase ATR. Analysis of hypomorphic mutants suggested the existence of crossover patterning defects, but it was not possible to assess this in null mutants because of maternal-effect embryonic lethality. To overcome this lethality, we constructed mei-41 null mutants in which we expressed wild-type Mei-41 in the germline after completion of meiotic recombination, allowing progeny to survive. We find that crossovers are decreased to about one-third of wild-type levels, but the reduction is not uniform, being less severe in the proximal regions of chromosome 2L than in medial or distal 2L or on the X chromosome. None of the crossovers formed in the absence of Mei-41 require Mei-9, the presumptive meiotic resolvase, suggesting that Mei-41 functions everywhere, despite the differential effects on crossover frequency. Interference appears to be significantly reduced or absent in mei-41 mutants, but the reduction in crossover density in centromere-proximal regions is largely intact. We propose that crossover patterning is achieved in a stepwise manner, with the crossover suppression related to proximity to the centromere occurring prior to and independently of crossover designation and enforcement of interference. In this model, Mei-41 has an essential function in meiotic recombination after the centromere effect is established but before crossover designation and interference occur.

Categories: Genetics News Feed

Genes Important for Schizosaccharomyces pombe Meiosis Identified Through a Functional Genomics Screen [Genome Integrity and Transmission]

January 29, 2018 - 9:17am

Meiosis is a specialized cell division that generates gametes, such as eggs and sperm. Errors in meiosis result in miscarriages and are the leading cause of birth defects; however, the molecular origins of these defects remain unknown. Studies in model organisms are beginning to identify the genes and pathways important for meiosis, but the parts list is still poorly defined. Here we present a comprehensive catalog of genes important for meiosis in the fission yeast, Schizosaccharomyces pombe. Our genome-wide functional screen surveyed all nonessential genes for roles in chromosome segregation and spore formation. Novel genes important at distinct stages of the meiotic chromosome segregation and differentiation program were identified. Preliminary characterization implicated three of these genes in centrosome/spindle pole body, centromere, and cohesion function. Our findings represent a near-complete parts list of genes important for meiosis in fission yeast, providing a valuable resource to advance our molecular understanding of meiosis.

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Cooperative Control of Ecdysone Biosynthesis in Drosophila by Transcription Factors Seance, Ouija Board, and Molting Defective [Gene Expression]

January 29, 2018 - 9:17am

Ecdysteroids are steroid hormones that control many aspects of development and physiology. During larval development, ecdysone is synthesized in an endocrine organ called the prothoracic gland through a series of ecdysteroidogenic enzymes encoded by the Halloween genes. The expression of the Halloween genes is highly restricted and dynamic, indicating that their spatiotemporal regulation is mediated by their tight transcriptional control. In this study, we report that three zinc finger-associated domain (ZAD)-C2H2 zinc finger transcription factors—Séance (Séan), Ouija board (Ouib), and Molting defective (Mld)—cooperatively control ecdysone biosynthesis in the fruit fly Drosophila melanogaster. Séan and Ouib act in cooperation with Mld to positively regulate the transcription of neverland and spookier, respectively, two Halloween genes. Remarkably, loss-of-function mutations in séan, ouib, or mld can be rescued by the expression of neverland, spookier, or both, respectively. These results suggest that the three transcription factors have distinct roles in coordinating the expression of just two genes in Drosophila. Given that neverland and spookier are located in constitutive heterochromatin, Séan, Ouib, and Mld represent the first example of a transcription factor subset that regulates genes located in constitutive heterochromatin.

Categories: Genetics News Feed

The X-linked 1.688 Satellite in Drosophila melanogaster Promotes Specific Targeting by Painting of Fourth [Gene Expression]

January 29, 2018 - 9:17am

Repetitive DNA, represented by transposons and satellite DNA, constitutes a large portion of eukaryotic genomes, being the major component of constitutive heterochromatin. There is a growing body of evidence that it regulates several nuclear functions including chromatin state and the proper functioning of centromeres and telomeres. The 1.688 satellite is one of the most abundant repetitive sequences in Drosophila melanogaster, with the longest array being located in the pericentromeric region of the X-chromosome. Short arrays of 1.688 repeats are widespread within the euchromatic part of the X-chromosome, and these arrays were recently suggested to assist in recognition of the X-chromosome by the dosage compensation male-specific lethal complex. We discovered that a short array of 1.688 satellite repeats is essential for recruitment of the protein POF to a previously described site on the X-chromosome (PoX2) and to various transgenic constructs. On an isolated target, i.e., an autosomic transgene consisting of a gene upstream of 1.688 satellite repeats, POF is recruited to the transgene in both males and females. The sequence of the satellite, as well as its length and position within the recruitment element, are the major determinants of targeting. Moreover, the 1.688 array promotes POF targeting to the roX1-proximal PoX1 site in trans. Finally, binding of POF to the 1.688-related satellite-enriched sequences is conserved in evolution. We hypothesize that the 1.688 satellite functioned in an ancient dosage compensation system involving POF targeting to the X-chromosome.

Categories: Genetics News Feed

Histone Demethylase Activity of Utx Is Essential for Viability and Regulation of HOX Gene Expression in Drosophila [Communications]

January 29, 2018 - 9:17am

The trimethylation of histone H3 at lysine 27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) is essential for the repression of Polycomb target genes. However, the role of enzymatic demethylation of H3K27me3 by the KDM6-family demethylases Utx, Uty, and JmjD3 is less clear. Studies in both mice and worms led to the proposal that KDM6 proteins, but not their H3K27me3 demethylase activity, is critical for normal development. Here, we investigated the requirement of the demethylase activity of the single KDM6 family member Utx in Drosophila. We generated Drosophila expressing a full-length but catalytically inactive Utx protein and found that these mutants show the same phenotypes as animals lacking the Utx protein. Specifically, animals lacking maternally deposited active Utx demethylase in the early embryo show stochastic loss of HOX gene expression that appears to be propagated in a clonal fashion. This suggests that Utx demethylase activity is critical for the removal of ectopic H3K27 trimethylation from active HOX genes during the onset of zygotic gene transcription, and thereby prevents the inappropriate installment of long-term repression by Polycomb. Conversely, maternally deposited catalytically active Utx protein suffices to permit animals that lack zygotic expression of enzymatically active Utx to develop into morphologically normal adults, which eclose from the pupal case but die shortly thereafter. Utx demethylase activity is therefore also essential to sustain viability in adult flies. Together, these analyses identify the earliest embryonic stages and the adult stage as two phases during the Drosophila life cycle that critically require H3K27me3 demethylase activity.

Categories: Genetics News Feed

Dissecting the Roles of the Calcineurin Pathway in Unisexual Reproduction, Stress Responses, and Virulence in Cryptococcus deneoformans [Cellular Genetics]

January 29, 2018 - 9:17am

The Ca2+/calmodulin-dependent protein phosphatase calcineurin orchestrates sexual reproduction, stress responses, and virulence via branched downstream pathways in the opportunistic human fungal pathogen Cryptococcus neoformans. The calcineurin-binding protein Cbp1, the calcineurin temperature suppressor Cts1, the calcineurin-responsive zinc finger transcription factor Crz1, and the calcineurin targets Pbp1, Tif3, and Puf4, all function downstream of calcineurin to orchestrate distinct cellular processes. To elucidate how the calcineurin pathway regulatory network governs unisexual reproduction, stress responses, and virulence, we have analyzed the self-filamentous C. deneoformans strain, XL280α, and generated double mutants of these calcineurin downstream genes. We demonstrated that calcineurin governs unisexual reproduction at different sexual developmental stages, in which the initiation of the yeast–hyphal morphological transition is independent of Crz1, whereas the sporulation process is dependent on Crz1. Calcineurin-dependent unisexual reproduction is independent of the pheromone response pathway. Crz1 synergistically interacts with different calcineurin downstream targets in responding to ER, high-calcium, and cell wall stresses. We observed a widespread synergy suggesting that these proteins function in complex branched pathways downstream of calcineurin with some functional redundancy, which may allow efficient signaling network rewiring within the pathway for prompt adaptation to changing environments. Finally, we showed that deletion of PBP1 or TIF3 in the cna1 mutant background conferred a modest level of growth tolerance at 37°, but that the cna1 pbp1 and cna1 tif3 double mutants were both avirulent, suggesting that calcineurin may control virulence via mechanisms beyond thermotolerance.

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Compensatory Internalization of Pma1 in V-ATPase Mutants in Saccharomyces cerevisiae Requires Calcium- and Glucose-Sensitive Phosphatases [Cellular Genetics]

January 29, 2018 - 9:17am

Loss of V-ATPase activity in organelles, whether through V-ATPase inhibition or V-ATPase (vma) mutations, triggers a compensatory downregulation of the essential plasma membrane proton pump Pma1 in Saccharomyces cerevisiae. We have previously determined that the α-arrestin Rim8 and ubiquitin ligase Rsp5 are essential for Pma1 ubiquination and endocytosis in response to loss of V-ATPase activity. Here, we show that Pma1 endocytosis in V-ATPase mutants does not require Rim101 pathway components upstream and downstream of Rim8, indicating that Rim8 is acting independently in Pma1 internalization. We find that two phosphatases, the calcium-responsive phosphatase calcineurin and the glucose-sensitive phosphatase Glc7 (PP1), and one of the Glc7 regulatory subunits Reg1, exhibit negative synthetic genetic interactions with vma mutants, and demonstrate that both phosphatases are essential for ubiquitination and endocytic downregulation of Pma1 in these mutants. Although both acute and chronic loss of V-ATPase activity trigger the internalization of ~50% of surface Pma1, a comparable reduction in Pma1 expression in a pma1-007 mutant neither compensates for loss of V-ATPase activity nor stops further Pma1 endocytosis. The results indicate that the cell surface level of Pma1 is not directly sensed and that internalized Pma1 may play a role in compensating for loss of V-ATPase-dependent acidification. Taken together, these results provide new insights into cross talk between two major proton pumps central to cellular pH control.

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Tissue-Specific Gene Inactivation in Xenopus laevis: Knockout of lhx1 in the Kidney with CRISPR/Cas9 [Developmental and Behavioral Genetics]

January 29, 2018 - 9:17am

Studying genes involved in organogenesis is often difficult because many of these genes are also essential for early development. The allotetraploid frog, Xenopus laevis, is commonly used to study developmental processes, but because of the presence of two homeologs for many genes, it has been difficult to use as a genetic model. Few studies have successfully used CRISPR in amphibians, and currently there is no tissue-targeted knockout strategy described in Xenopus. The goal of this study is to determine whether CRISPR/Cas9-mediated gene knockout can be targeted to the Xenopus kidney without perturbing essential early gene function. We demonstrate that targeting CRISPR gene editing to the kidney and the eye of F0 embryos is feasible. Our study shows that knockout of both homeologs of lhx1 results in the disruption of kidney development and function but does not lead to early developmental defects. Therefore, targeting of CRISPR to the kidney may not be necessary to bypass the early developmental defects reported upon disruption of Lhx1 protein expression or function by morpholinos, antisense RNA, or dominant negative constructs. We also establish a control for CRISPR in Xenopus by editing a gene (slc45a2) that when knocked out results in albinism without altering kidney development. This study establishes the feasibility of tissue-specific gene knockout in Xenopus, providing a cost-effective and efficient method for assessing the roles of genes implicated in developmental abnormalities that is amenable to high-throughput gene or drug screening techniques.

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A Common Pathway of Root Growth Control and Response to CLE Peptides Through Two Receptor Kinases in Arabidopsis [Developmental and Behavioral Genetics]

January 29, 2018 - 9:17am

Cell–cell communication is essential for plants to integrate developmental programs with external cues that affect their growth. Recent advances in plant signaling have uncovered similar molecular mechanisms in shoot, root, and vascular meristem signaling that involve receptor-like kinases and small, secreted peptides. Here, we report that the receptor-like kinases TOAD2/RPK2 and RPK1 regulate root growth by controlling cell proliferation and affecting meristem size. Two types of developmental alterations were observed upon exogenous CLE peptide application. The first type was detected in all plants treated, and comprise increased proliferative activity of cells in the stem cell niche and a delay of progression in differentiation of daughter cells. The second type was changes specific to the genotypes that are sensitive to CLE-driven root meristem inhibition and include a large decrease in the occurrence of cell divisions in longitudinal files, correlating with shorter meristems and cessation of root growth. The root meristems of toad2/rpk2 mutant plants are insensitive to the inhibitory effect of CLE17 peptide treatment, consistent with TOAD2/RPK2 function as a receptor for CLE peptides. In addition, a strong reduction in the expression of RPK1 protein upon CLE treatment, dependent on TOAD2/RPK2, suggests that these two RLKs mediate CLE signaling in a common pathway to control root growth.

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Drosophila Syd-1 Has RhoGAP Activity That Is Required for Presynaptic Clustering of Bruchpilot/ELKS but Not Neurexin-1 [Developmental and Behavioral Genetics]

January 29, 2018 - 9:17am

Syd-1 proteins are required for presynaptic development in worm, fly, and mouse. Syd-1 proteins in all three species contain a Rho GTPase activating protein (GAP)-like domain of unclear significance: invertebrate Syd-1s are thought to lack GAP activity, and mouse mSYD1A has GAP activity that is thought to be dispensable for its function. Here, we show that Drosophila melanogaster Syd-1 can interact with all six fly Rhos and has GAP activity toward Rac1 and Cdc42. During development, fly Syd-1 clusters multiple presynaptic proteins at the neuromuscular junction (NMJ), including the cell adhesion molecule Neurexin (Nrx-1) and the active zone (AZ) component Bruchpilot (Brp), both of which Syd-1 binds directly. We show that a mutant form of Syd-1 that specifically lacks GAP activity localizes normally to presynaptic sites and is sufficient to recruit Nrx-1 but fails to cluster Brp normally. We provide evidence that Syd-1 participates with Rac1 in two separate functions: (1) together with the Rac guanine exchange factor (RacGEF) Trio, GAP-active Syd-1 is required to regulate the nucleotide-bound state of Rac1, thereby promoting Brp clustering; and (2) Syd-1, independent of its GAP activity, is required for the recruitment of Nrx-1 to boutons, including the recruitment of Nrx-1 that is promoted by GTP-bound Rac1. We conclude that, contrary to current models, the GAP domain of fly Syd-1 is active and required for presynaptic development; we suggest that the same may be true of vertebrate Syd-1 proteins. In addition, our data provide new molecular insight into the ability of Rac1 to promote presynaptic development.

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Regulated Alternative Splicing of Drosophila Dscam2 Is Necessary for Attaining the Appropriate Number of Photoreceptor Synapses [Developmental and Behavioral Genetics]

January 29, 2018 - 9:17am

How the brain makes trillions of synaptic connections using a genome of only 20,000 genes is a major question in modern neuroscience. Alternative splicing is one mechanism that can increase the number of proteins produced by each gene, but its role in regulating synapse formation is poorly understood. In Drosophila, photoreceptors form a synapse with multiple postsynaptic elements including lamina neurons L1 and L2. L1 and L2 express distinct isoforms of the homophilic repulsive protein Dscam2, and since these isoforms cannot bind to each other, cell-specific expression has been proposed to be necessary for preventing repulsive interactions that could disrupt the synapse. Here, we show that the number of synapses are reduced in flies that express only one isoform, and L1 and L2 dendritic morphology is perturbed. We propose that these defects result from inappropriate interactions between L1 and L2 dendrites. We conclude that regulated Dscam2 alternative splicing is necessary for the proper assembly of photoreceptor synapses.

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