Proper development of the cortex, the command center of the brain, entails extensive production of neurons. This is largely achieved through the robust asymmetric division of radial glial progenitor cells (RGPCs) residing in the ventricular zone (VZ) of the developing cortex. While excellent progress has been made over the past twenty years in our understanding of RGPC division and neurogenesis in the developing cortex, our knowledge of the precise regulation and function of the centrosome, a key subcellular organelle for microtubule organization, cell division and ciliogenesis, during cortical neurogenesis remains limited. The goal of this application is to fill this knowledge gap, which wil also be crucial for understanding the etiology and pathophysiology of microcephaly, a neuro-developmental disorder that is characterized by small brain size as a result of deficient neuron production in the developing cortex. To date, at least eight autosomal recessive primary microcephaly (MCPH) loci and seven genes have been identified for autosomal recessive primary microcephaly (MCPH). Remarkably, all the defined MCPH genes encode centrosomal proteins, underscoring the unique importance of proper centrosome regulation and function in the production of normal neuron populations in the developing cortex. The central hypothesis is that the mature centrosome is essential for maintaining RGPCs in the VZ - a progenitor cell niche - and ensuring their proper division and survival in the developing cortex. This hypothesis has been formulated on the basis of the strong published and preliminary data produced in the applicant's laboratory. Guided by preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Reveal centrosome properties and behavior in interphase and mitotic RGPCs; 2) Define the functions of the centrosome in RGPCs; and, 3) Explore the mechanisms that regulate centrosome behavior in RGPCs. The experimental focus of this application is to provide a comprehensive understanding of the behavior, function and regulation of the centrosome in RGPCs as they proceed through the cell cycle to produce neurons and link it to microcephaly, using state-of-the- art imaging and mouse genetic approaches. As of this writing, few such studies have been reported. Accomplishing the aims in this project will not only provide important insights into RGPC division and cortical neurogenesis, but also help to define the cellular basis of microcephaly caused by genetic abnormalities, and thereby provide new ideas for early diagnosis and treatment.
The proposed research is relevant to public health because knowledge of the regulation and function of the centrosome in neural progenitor cell division and cortical neurogenesis will facilitate our understanding of microcephaly linked to genetic abnormalities or prenatal exposure to drug abuse. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human disability.
