Defining the cell type-specific role of miR-9-2 in telencephalon development

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PROJECT SUMMARY Dysregulation of gene networks during development can lead to organ malformation, dysfunction and disease, especially neurological diseases such as schizophrenia, Huntington’s and Alzheimer’s disease. Thus, a more comprehensive understanding of the gene regulatory networks that are active during development of the central nervous system are needed to better understand disease etiology and treatment. The long-term goal of this proposal is to define the role of the microRNA miR-9-2 in brain development, function and disease utilizing in vivo knock-out mouse models. My preliminary data show that loss of miR-9-2 during development results in severely malformed forebrains in mice in a gene dose-dependent manner. Based on this and previous studies, I hypothesize that miR-9-2 is a critical regulator of gene networks that instruct neural progenitor proliferation, differentiation and survival. Here, using a combination of transcriptomic, genomic and histological methods, I will uncover the genes, genomic regulatory elements and cellular processes regulated by miR-9-2 during brain development to define the specific role of this important microRNA. Additionally, I will uncover upstream regulators of miR-9-2 expression by investigating the role of a deeply conserved cis-regulatory element, or enhancer in modulating miR-9-2 expression during development. The proposed research is significant because it will provide a comprehensive understanding of the gene networks, cell populations, and brain structures under miR-9-2 regulation, give insight into the regulation of miR-9-2 expression and inform on the consequences of miR-9-2 dysregulation that lead to neurological disease.