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

Seattle Children'S Hospital, Seattle WA

Investigators

Abstract

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.