The function of YPEL3 in the nervous system

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 DESCRIPTION (provided by applicant): The Undiagnosed Disease Network (UDN) has identified a mutation in the Yippee-like 3 (YPEL3) gene that potentially causes a rare human condition manifesting a number of neurological symptoms. Although the discovery has opened the opportunity to diagnose and treat this rare human disease, there is an enormous knowledge gap to be filled in order to understand the pathogenesis of this human condition and for designing potential treatments. This is largely due to the lack of knowledge on the cellular and molecular functions of YPEL3. The long-term goal is to understand the mechanism of pathogenesis caused by human mutations in the YPEL3 gene and to design therapeutic approaches to treat this rare disease. The objective of this application is to establish an in vivo Drosophila model for identifying the cellular and molecular functions of YPEL3 in the development of nervous system. Drosophila is advantageous in studying YPEL3 functions because it provides excellent tools for dissecting cellular and molecular functions and enables us to avoid possible redundancy from other YPEL genes in mammals. The central hypothesis is that YPEL3 regulates peripheral nerve development by modulating pre-mRNA splicing. This hypothesis has been deduced from the nature of the human mutation, the symptoms displayed by the patient, and the literature related to the YPEL gene family. The rationale for the proposed research is that since YPEL3 is well-conserved between human and Drosophila, understanding the cellular and molecular functions of YPEL3 in Drosophila will aid to develop effective treatment of the human diseases related to YPEL3 mutations. The hypothesis will be tested under two specific aims: 1) Identify the roles of YPEL3 in nerve development; and 2) Identify the molecular functions of YPEL3. Under the first aim, loss-of-function mutants of YPEL3 will be generated and tested for morphological alterations of glial wrapping and axon branching in peripheral nerves. Under the second aim, localization and phosphorylation of nuclear splicing regulators will be determined in glia and neurons of YPEL3 mutant. The contribution of the proposed research will be significant because it will provide not only the mechanistic insight into how YPEL3 mutations lead to pathogenesis but also a genetically amenable in vivo model system for studyin YPEL3-related diseases, facilitating the development of therapeutics. The research proposed in this application is innovative, because it integrates the fragmented information into a cohesive novel concept, and because its use of Drosophila as a model organism to avoid possible redundancy caused by other YPEL homologs as is the case in mammals.