Genetic analysis of the adenylate forming domain protein DIP-2 in C. elegans neuronal development

线虫神经元发育中腺苷酸形成域蛋白 DIP-2 的遗传分析

• 批准号: RGPIN-2018-06790
• 负责人: Colavita, Antonio
• 金额: $ 5.25万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=746576
• 关键词: Genetic; analysis; adenylate; forming; domain

Neurons exhibit a diverse array of morphologies that contribute to both connectivity and function. Neuronal morphology is established during critical developmental periods when cytoskeletal structures and rearrangements mediate the specification of axon and dendritic processes, wiring of neuronal connections and the activity-dependent and independent elaboration of dendritic arbours. Post-developmentally, neurons are very long lived and, while shown to be capable of plasticity-promoting remodeling of dendritic structures, are thought to maintain relatively stable morphologies over adulthood. The molecular mechanisms that maintain neuronal morphology remain poorly understood.My lab is interested in how neuronal morphology is established and maintained using the anatomically simple nervous system of C. elegans, a microscopic worm, as a model system. We have recently found that mutations in dip-2, the worm orthologue of Disco Interacting Protein-2 (DIP2), display strong neuronal morphology defects in multiple types of neurons suggesting a central role in both nervous system development and maintenance. DIP2 proteins belong to a highly conserved but poorly understood family of adenylate forming domain proteins. Our objective with this Discovery Grant is to understand how the adenylate forming domain protein DIP-2 acts to maintain neuronal morphology. First, we propose to undertake unbiased gene/protein discovery' approaches to identify mutations in genes that display dip-2-like neuronal morphology defects or aberrant DIP-2 protein localization (Aim 1A) and new components of DIP-2 protein complexes in neurons (Aim 1B) and second, characterize the resulting genes/protein candidates for direct roles in DIP-2 mediated neuronal maintenance (Aim 2). Successful completion of these aims should lead to fundamental insight into how neurons maintain their morphology during the normal aging process.

神经元表现出各种各样的形态，这些形态既有助于连通性和功能。当细胞骨架结构和重排介导轴突和树突过程的规范，神经元连接的接线以及活性依赖性和独立的树突状arbours的定义时，神经元形态是在关键发育期间建立的。发达后的神经元很长很长，虽然证明能够对树突状结构进行塑性重塑，但被认为在成年期间保持相对稳定的形态。维持神经元形态的分子机制仍然很少了解。我们最近发现，DIP-2中的突变是迪斯科相互作用蛋白-2（DIP2）的蠕虫直系同源物（DIP2），在多种类型的神经元中显示出强的神经元形态缺陷，这表明在神经系统发育和维持中都具有核心作用。 DIP2蛋白属于一个高度保守但知之甚少的腺苷酸元蛋白家族。我们对这一发现赠款的目标是了解腺苷酸形成域蛋白DIP-2如何作用以维持神经元形态。 First, we propose to undertake unbiased gene/protein discovery' approaches to identify mutations in genes that display dip-2-like neuronal morphology defects or aberrant DIP-2 protein localization (Aim 1A) and new components of DIP-2 protein complexes in neurons (Aim 1B) and second, characterize the resulting genes/protein candidates for direct roles in DIP-2 mediated neuronal maintenance (Aim 2）。这些目标的成功完成应导致对神经元在正常衰老过程中如何保持其形态的基本见解。