Translational Control of Early Neurogenesis in Drosophila

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DESCRIPTION (provided by applicant): An early step in neurogenesis is the generation of neuronal precursor cells from the naive neuroepithelium. Although transcription factors and several signaling pathways that promote early neurogenesis have been identified, the mechanisms that ensure the generation of precise numbers of neuronal precursors from the neuroepithelial cells remain to be further defined. One of the best model systems for understanding early neurogenesis is sensory organ precursor (SOP) formation in the Drosophila peripheral nervous system. A small number of cells, known as the proneural cluster, express proneural genes that encode basic helix loop helix (bHLH) proteins and become competent to develop into SOPs. The SOP emerges from the proneural cluster through the actions of "neurogenic" genes (e.g., Notch and Delta) that maintain proneural gene expression at high levels in the SOP and at low levels in adjacent epithelial cells. The ligand Delta binds to the Notch receptor, which in turn regulates the differential expression of proneural genes through the actions of Suppressor of hairless [Su(H)] and the Enhancer of split complex. Senseless (Sens), a nuclear protein with four zinc fingers that is required to upregulate and maintain proneural gene expression in SOPs, is expressed at a high level in SOPs. In adjacent epithelial cells in the proneural cluster, Sens is expressed at a low level and suppresses proneural gene expression. These differences in the expression and function of Sens are essential for proper SOP formation. The mechanism of differential regulation of these genes required for the accurate production of neuronal precursor cells is unclear. Recently, we generated microRNA-9a loss-of- function mutant flies and found that microRNA-9a normally inhibits neuronal fate in non-SOP cells by downregulating Sens expression. In this application, we propose to further dissect the feedback loops between proneural genes and microRNA-9a. Using genetic screens, we will also identify other key targets of microRNA- 9a, including potential novel players important for early neurogenesis. Since many microRNAs are 100% conserved at the nucleotide level from flies to mammals, our findings will have important implications for mammalian neurogenesis as well and may provide novel insights into neurodevelopmental disorders.