The function of YPEL3 in the nervous system

 描述（由申请人提供）：未诊断疾病网络（UDN）已经确定了Yippee样3（YPEL 3）基因的突变，该突变可能导致罕见的人类疾病，表现出许多神经系统症状。虽然这一发现为诊断和治疗这种罕见的人类疾病提供了机会，但为了了解这种人类疾病的发病机制并设计潜在的治疗方法，还有巨大的知识空白需要填补。这在很大程度上是由于缺乏对YPEL 3的细胞和分子功能的了解。长期目标是了解人类YPEL 3基因突变引起的发病机制，并设计治疗这种罕见疾病的治疗方法。本申请的目的是建立一种体内 鉴定YPEL 3在神经系统发育中的细胞和分子功能的果蝇模型。果蝇在研究YPEL 3功能方面是有利的，因为它为解剖细胞和分子功能提供了极好的工具，并使我们能够避免哺乳动物中其他YPEL基因的可能冗余。核心假设是YPEL 3通过调节前体mRNA剪接来调节周围神经发育。这一假设是从人类突变的性质、患者表现出的症状以及与YPEL基因家族相关的文献中推导出来的。这项研究的基本原理是，由于YPEL 3在人类和果蝇之间具有良好的保守性，因此了解YPEL 3在果蝇中的细胞和分子功能将有助于开发与YPEL 3突变相关的人类疾病的有效治疗方法。该假设将在两个特定目标下进行测试：1）确定YPEL 3在神经发育中的作用; 2）确定YPEL 3的分子功能。在第一个目标下，将产生YPEL 3的功能丧失突变体，并测试周围神经中胶质包裹和轴突分支的形态学改变。在第二个目标下，将确定YPEL 3突变体的神经胶质细胞和神经元中核剪接调节因子的定位和磷酸化。拟议的研究的贡献将是显着的，因为它不仅提供了机械的见解， YPEL 3突变如何导致发病机制，也是研究YPEL 3相关疾病的遗传学适用的体内模型系统，促进治疗方法的发展。在本申请中提出的研究是创新的，因为它将碎片化的信息整合到一个有凝聚力的新概念中，并且因为它使用果蝇作为模式生物，以避免其他YPEL同系物引起的可能冗余，就像哺乳动物中的情况一样。

 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.