Molecular mechanisms underlying retinal development

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The retina is a thin, sensory tissue lining the back of the eye comprised of 5 major classes of neurons and one glial cell type. Due to its simple cellular composition and organization, and because it is well suited to experimental manipulation, the retina represents an excellent model system for addressing questions relating to neural development. Our research program is centered on the mechanisms that regulate retinal development. The work in this proposal will examine the role of microRNAs in the regulation of a key regulator of retinal development, Pax6. MicroRNAs are a large class of small non-coding RNAs that function as sequence-specific guides to regulate transcriptional programs. Because of their ability to impose rapid and tight control of gene expression, microRNAs represent an important developmental regulatory mechanism. In mutant retinas that cannot properly synthesize microRNAs, there are defects in retinal progenitor proliferation, competency, cell survival, migration and differentiation. Pax6 is an ideal target to study microRNA regulation because it is highly sensitive to perturbations in gene dosage: too little or too much Pax6 is detrimental to normal retinal development. Furthermore, studies in the endocrine pancreas and subventricular zone of the developing forebrain where Pax6 is also expressed have implicated microRNAs as important regulators of Pax6. Here we will identify the cohort of microRNAs that specifically target Pax6 in the developing retina and developing eye fields. Experiments will be performed using molecular genetic approaches in vitro and in vivo to determine the role of microRNAs on Pax6 expression and function. This work adds to our basic understanding of the mechanisms underlying gene function and addresses an area of retinal biology that is currently poorly understood. It also serves as a general model for understanding the role of microRNA regulation during developmental processes.