Project 6: Regulation and Function of Extended 3' UTR Transcripts in the Nervous System

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PROJECT SUMMARY/ABSTRACT Regulation and Function of Extended 3´ UTR Transcripts in the Nervous System More than 50% of genes in diverse organisms undergo Alternative Cleavage and PolyAdenylation (APA) to generate multiple 3´ UTR mRNA isoforms. Thousands of novel extended 3´ UTRs have been recently identified to be preferentially expressed in the nervous system of fly, mouse and human. Such a pervasive and cell-specific event is likely to have wide-ranging physiologically relevant consequences for nervous system development, maintenance and disease. However, to date, few functional roles for extended 3´ UTRs have been identified. The long-term objectives are to uncover functions for these extended 3´ UTR isoforms in the nervous system, and elucidate the mechanisms of their biogenesis and biological activity. The focus is on a set of genes that play established roles in axon guidance. More than ten genes with roles in axon guidance express short and extended 3´ UTR isoforms, suggesting that APA is an important regulator for this key neurodevelopmental event. Some of these genes have direct relevance to human disease. For instance, mutations in calmodulin genes are implicated in multiple cardiac defects in humans. To investigate extended 3´ UTR function, CRISPR genome editing is employed to specifically delete these isoforms in Drosophila. This approach has been established, and preliminary work has uncovered that impairment of an extended 3´ UTR isoform, while leaving the short 3´ UTR isoforms intact, can impair nervous system development. In Aim 1, this approach is expanded to cam, the Drosophila calmodulin gene. In Aim 2, the role that chromatin modifications have on the biogenesis of extended 3´ UTRs is investigated. This builds upon ongoing work on the mechanism through which the ELAV regulates 3´ UTR extension. Overall, this work will establish APA as a crucial mechanism governing multiple genes that control axon guidance.