Control of gene expression during neuronal development

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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.