Investigating the function of a ciliary protein in neural development

PROJECT SUMMARY/ABSTRACT Synapses serve as vital intercellular connections facilitating rapid and accurate transmission of information between neurons. Successful nervous system development is dependent on proper synapse formation, an intricate and highly coordinated process regulated by complex cellular and molecular mechanisms. Elucidating the mechanistic underpinnings of synapse formation holds significant promise in advancing our understanding of neurodevelopmental and neurodegenerative disorders. The purpose of this proposal is to uncover novel molecular mechanisms involved in synapse formation, particularly as it pertains to neurological disorders. Using genetics, super resolution microscopy, and in-vivo unbiased proteomics, I will explore novel mechanisms that regulate synapse formation in the nervous system. My doctoral training will provide the essential foundations for me to become a successful independent investigator. Our preliminary studies have led to investigating a ciliary protein with poorly understood function in cilia. We have found this ciliary protein is the most prominent hit in affinity-purification proteomics data with RPM-1. RPM-1 is a known regulator of nervous system development and the human ortholog MYCBP2 is involved in a neurodevelopmental disorder. Using C. elegans as my model organism, research in Aim 1 will investigate the function of this ciliary protein in GABAergic neurons and elucidate its relationship with the RPM-1 ubiquitin ligase and signaling hub. I hypothesize that this ciliary protein has a non-ciliary function in synapse formation of GABAergic motor neurons and is involved in the RPM-1 signaling network. Studies in Aim 2 will focus examine the functional role of this protein in ciliated neurons for the first time using the C. elegans model organism. I will investigate how this player shapes ciliated neuron development by using genetics and neuron-specific transgenic approaches. Completion of these studies will provide me with the necessary knowledge and skillset to further investigate genetic regulatory mechanisms that shape neurodevelopment.