Control of gene expression during neuronal development

神经元发育过程中基因表达的控制

• 批准号: RGPIN-2018-04520
• 负责人: Park, Jeehye
• 金额: $ 2.7万
• 依托单位: University of Toronto
• 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=761249
• 关键词: Control; gene; expression; during; neuronal

Neuronal development is a complex process that involves determination of neuronal identity, neuronal migration into proper location, axonal development and differentiation, and the development of synaptic connections with neighboring neurons. These processes are regulated by the genetic program. Gene expression changes induced by stimuli from neighboring cells and the environment also contribute to neuronal development. My research program aims to understand how gene expression program regulates neuronal development. Much effort has been devoted to identifying the transcription factors that control neuronal development, but there has been limited progress on studies how RNA binding proteins (RBPs) that are involved in post-transcriptional regulation contribute to neuronal development. RNA splicing regulates the expression of single genes by generating different transcripts and controlling the expression levels of transcript isoforms. These variations contribute to proteome diversity and abundance, ultimately leading to different neuronal properties and functions. How RBPs regulate RNA splicing and produce such a striking complexity of neuronal types and functions remains to be determined. Our long-term goal is to address the role of RBPs in RNA splicing during neuronal development. Towards this goal, my lab studies the function of an RBP called Matrin 3 (MATR3) in mouse neurons. My lab and others demonstrated that MATR3 regulates RNA splicing in human cells. We also found that MATR3 is highly expressed in the nervous system of the mouse embryo, and is required for early mouse development. However, little is known about the role of MATR3 in RNA splicing in a physiological context. In this proposal, we will investigate the function of MATR3 in RNA regulation in mouse neurons. Our first objective is to examine the changes in RNA splicing landscape upon loss of MATR3 to determine the role of MATR3 in splicing regulation during neuronal development. Our second objective is to investigate the molecular mechanism by which MATR3 regulates RNA splicing through the identification of RNA targets and protein interactors. Our third objective is to determine the physiological consequences upon loss of MATR3 on neuronal development, which will provide insight into the effect of MATR3-associated RNA splicing on neuronal development. The proposed research will enhance our understanding of the in vivo function of MATR3 in RNA splicing and provide new knowledge of how it contributes to the properties and functions of neurons during development. Our research will provide a framework to study how an RBP controls RNA splicing and regulates gene expression system, contributing to proteome diversity and abundance during neuronal development. The discoveries from this work will advance the fields of RNA biology and neurodevelopment.

神经元发育是一个复杂的过程，涉及确定神经元身份，神经元迁移到适当的位置，轴突发育和分化，以及与相邻神经元的突触连接的发育。这些过程是由遗传程序控制的。来自邻近细胞和环境的刺激诱导的基因表达变化也有助于神经元发育。我的研究项目旨在了解基因表达程序如何调节神经元发育。 目前，研究者们已经对控制神经元发育的转录因子进行了大量的研究，但对于参与转录后调控的RNA结合蛋白（RBP）如何促进神经元发育的研究进展有限。RNA剪接通过产生不同的转录物并控制转录物同种型的表达水平来调节单个基因的表达。这些变化有助于蛋白质组的多样性和丰度，最终导致不同的神经元特性和功能。RBP如何调节RNA剪接并产生如此惊人的神经元类型和功能的复杂性仍有待确定。我们的长期目标是解决RBP在神经元发育过程中RNA剪接中的作用。 为了实现这一目标，我的实验室研究了一种名为Matrin 3（MATR 3）的RBP在小鼠神经元中的功能。我的实验室和其他人证明了MATR3调节人类细胞中的RNA剪接。我们还发现MATR 3在小鼠胚胎的神经系统中高度表达，并且是小鼠早期发育所必需的。然而，很少有人知道MATR 3在RNA剪接在生理环境中的作用。在本研究中，我们将研究MATR 3在小鼠神经元RNA调控中的功能。我们的第一个目标是研究MATR 3缺失后RNA剪接格局的变化，以确定MATR 3在神经元发育过程中剪接调控中的作用。我们的第二个目标是通过鉴定RNA靶点和蛋白质相互作用物来研究MATR 3调节RNA剪接的分子机制。我们的第三个目标是确定MATR 3缺失对神经元发育的生理后果，这将为MATR 3相关RNA剪接对神经元发育的影响提供深入了解。拟议的研究将增强我们对MATR 3在RNA剪接中的体内功能的理解，并提供关于它如何在发育过程中对神经元的特性和功能做出贡献的新知识。我们的研究将为研究RBP如何控制RNA剪接和调节基因表达系统提供一个框架，从而有助于神经元发育过程中蛋白质组的多样性和丰富性。这项工作的发现将推动RNA生物学和神经发育领域的发展。