Friday, May 3, 2024
5/3/2024
This proposal addresses one of the most fundamental unsolved problems in vision: the molecular and cellular mechanism responsible for building and maintaining the light-sensitive organelle of vertebrate photoreceptor cells, the outer segment. The outer segment is a ciliary structure filled with a stack of disc membranes, which provide vast surfaces for light capture and harbor proteins comprising the phototransduction machinery. Discs are renewed on a daily basis in order to counteract the adverse effects of light exposure, and the fidelity of disc renewal is critical for maintaining photoreceptor health and normal vision. It is now well-established that the formation of each new disc begins with an evagination of the ciliary plasma membrane driven by an expansion of branched actin network in a mechanism akin the formation of lamellipodia in motile cells. What remain entirely unknown are the molecular mechanism that initiate the formation of each new disc with the striking periodicity of approximately 80 times per day in mammals. Pinpointing this mechanism is the overall goal of this application. Our recent work shows that this actin network is nucleated by the WAVE protein complex whose unique subunit composition is specifically fitted to perform this function. Because WAVE complexes mediate between the upstream signaling pathways and downstream actin networks, this opens doors to elucidating the entire mechanism responsible for the periodic assembly and disassembly of actin at the disc morphogenesis site. To accomplish this goal, we will combine the efforts of two laboratories, which will contribute unique expertise and two complementary models of genetically modified animals: mice and Xenopus frogs. Our proposed experiments will investigate the regulation of the actin cytoskeleton dynamics, including that in living photoreceptors, by two classes of regulatory molecules: small GTPases and phosphoinositides. Elucidating these mechanisms is critical for advancing our understanding of basic photoreceptor cell biology and pathobiological mechanisms underlying photoreceptor degeneration frequently associated with defects in outer segment morphogenesis.
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