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Elucidating the tissue specific functions of the splicing factor Caper in sensory neuron and motoneuron morphogenesis

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Project Summary/Abstract Alternative splicing is a fundamental gene regulatory mechanism that allows cells to significantly diversify their protein products, especially within the nervous system. Splicing defects, often caused by mutations that disrupt the function of RNA-binding proteins (RBPs), which regulate splicing, have increasingly been implicated in neurological disorders including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Interestingly, although the majority of RBPs are expressed widely within diverse tissue types, the nervous system is often particularly sensitive to their dysfunction. The long-term goal of this project is to begin to elucidate how aberrant splicing that results from the dysfunction of ubiquitously expressed RBPs, leads to tissue specific pathologies that underlie neurological diseases. To this end, the highly conserved splicing factor Caper will be used as a model. Caper is widely expressed throughout development and is required for the development and maintenance of Drosophila sensory neurons, and for development of the neuromuscular junction. Though little is known about the function of the human caper ortholog, the human Caper ortholog is expressed within the nervous system suggesting its neural functions may be conserved. The research proposed within this application will test the hypothesis that Caper regulates RNA targets in a tissue specific manner by participating in specific ribonucleoprotein complexes (RNPs) within the nervous system, and distinct RNPs in non-neural cell types. Using the highly tractable model, Drosophila, tissue specific molecular genetic manipulations will be used in conjunction with biochemistry to determine whether Caper associates with distinct splicing factors within the nervous system, as compared to non-neural tissues, to regulate alternative splicing. As a complementary approach, biochemistry and bioinformatics methods will be employed to determine whether Caper regulates distinct RNA targets depending on tissue type. Upon identifying Caper neural target RNAs, the consequences of Caper dysfunction on alternative isoform regulation for those RNA targets will be determined using bioinformatic methods that detect differential exon usage in a caper mutant background. Finally, the different spliceforms of Caper target mRNAs will be analyzed for their specific roles in neural development to begin to elucidate how alternative splicing contributes to the development and function of neurons. Since aberrant alternative splicing has emerged as a common theme in various neurodegenerative and neurodevelopmental disorders, the knowledge gained from this study has broad implications for understanding and treating neurological disorders.
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