MICRORNA-128 REGULATES THE PROLIFERATION AND NEUROGENESIS OF NEURAL PRECURSORS BY TARGETING PERICENTRIOLAR MATERIAL 1 (PCM1) IN THE DEVELOPING NEOCORTEX

Abstract

Formation of the neocortex during brain development requires coordinated transition of cell division from one that favors progenitor proliferation to that of neuronal differentiation undertaken by neural stem cells (NSCs). Disruption to this process may underlie structural changes in the brain associated with neuropsychiatric disorders including autism spectrum disorders (ASDs). Evidence that suggests microRNA (miR)-128, shown to be dysregulated in ASDs, to be a key regulator of NSC division is presented in this thesis. Manipulation of miR-128 in embryonic NSCs is carried out both in vitro and in vivo, in which upregulation increases neurogenesis and inhibits progenitor proliferation while downregulation has the opposite effect. Furthermore, pericentriolar material 1 (PCM1) is identified as the downstream molecular target of miR-128 that mediates the regulatory effect of the microRNA. Overexpression of miR-128 suppresses PCM1 at both mRNA and protein levels, and direct knockdown of PCM1 produces a phenocopy of miR-128 overexpression in NSCs. Finally, concomitant induction of PCM1 and miR-128 overexpression in NSCs rescued the phenotype associated with miR-128 overexpression, both in vitro and in vivo. Taken together, these results demonstrate a novel mechanism by which miR-128 regulates the proliferation and differentiation of NSCs in the developing neocortex.