From Susceptibility to Signals: How Extrinsic Cues Alter Stem and Progenitor Cell

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During eye development, progenitor cell proliferation and differentiation must be carefully orchestrated to ensure that an eye of the right size and cellular composition is generated. Retinal cancers and neurodegenerative diseases have been linked to an imbalance between proliferation and differentiation. This project investigates how extrinsic cues and intrinsic factors collaborate during the transition from proliferation to differentiation, probing the mechanisms that control eye growth and development in zebrafish. Zebrafish are particularly amenable to high- resolution imaging and embryological manipulations, allowing developmental events to be studied in real time and correlated with genetic, molecular, and cellular changes. SPECIFIC AIMS Aim 1: To investigate how cell cycle phase and components of the cell cycle machinery sensitize cells to local differentiation cues. This section asks whether retinal progenitor cells (RPCs) in G2/M are more susceptible to extrinsic differentiation cues. By transplanting mutant cells that hyperproliferate or cycle slowly into wild-type hosts, we will assess the susceptibility of cycling RPCs to environmental differentiation factors. Aim 2: To examine how retinoic acid signaling alters proliferation in a retinal stem cell niche. This aim is based on preliminary analysis of a novel small-eyed mutant in which retinoic acid (RA) target genes are upregulated throughout a stem cell niche in the peripheral retina. Using pharmacological and genetic approaches, it examines the impact of RA on proliferation, differentiation, and cell cycle kinetics. Aim 3: To probe the relationship between dorsal-ventral patterning and stem cell mediated growth in the zebrafish retina. The experiments in this aim employ gain- and loss-of-function approaches along with pharmacological manipulations to (1) assess whether Gdf6a-mediated patterning of the retina is required for maintenance of the ciliary marginal zone (CMZ), a retinal stem cell niche; and (2) investigate whether RA directly controls gene expression within the CMZ to directly modulate retinal stem and progenitor cell behaviors. Significance: By identifying mechanisms that coax retinal progenitor cells from proliferation to differentiation, this project will impact our understanding of growth, repair, and regeneration in the retina and the entire central nervous system.