Molecular and Cellular Mechanisms of Neocortical Neurogenesis

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DESCRIPTION (provided by applicant): Proper formation of the neocortex depends on the orderly production of a large number of neurons during embryonic development. Radial glial cells have been demonstrated to be a major population of neuronal progenitor cells in the developing neocortex. In addition to their well-characterized role in guiding radial migration of new-born neurons, radial glial cells divide in the ventricular zone to generate neurons. Precise control of radial glial cell division determines the number of neurons in the mature neocortex. Despite this fundamental role in neocortical development, the mechanisms that regulate radial glial progenitor cell division are poorly understood. The long-term goal of this project is to elucidate the molecular and cellular processes underlying radial glial progenitor cell division and neocortical neurogenesis. It is generally thought that radial glial progenitor cells initially divie symmetrically to amplify themselves and then divide asymmetrically to self- renew and give rise to neocortical neurons. A prevailing model of progenitor cell asymmetric division holds that proper orientation of the mitotic spindle relative to the axis of progenitor cell polarity ensures unequal segregation of critical cellular fate determinants between the two daughter cells. Recent studies from our lab and others have shown that the evolutionarily conserved partition defective (Par) protein complex regulates the symmetric versus asymmetric division of radial glial progenitor cells. Furthermore, we recently found that the duplicated mother and daughter centrosomes in asymmetrically dividing radial glial progenitor cells are differentially inherited b the two daughter cells dependent on the centrosome maturity and daughter cell fate specification. As the major microtubule-organizing center in animal cells, the centrosome is not only critical for the formation of the mitotic spindle, but also absolutely required for the formaton of a cilium, the cellular antennae that orchestrate important signaling pathways related to cell proliferation and differentiation. Based on these observations, the central hypothesis of this application is that the Par polarity complex regulates mitotic spindle orientation, mother versus daughter centrosome inheritance, and ciliogenesis in radial glial progenitor cells. Guided by strong preliminary data, this hypothesis will be tested by investigating the functions of the mPar protein complex in regulating: 1) mitotic spindle orientation in dividing radial glial progenitor cells, 2) mother versus daughter centrosome inheritance in dividing radial glial progenitor cells, and 3) ciliogenesis in dividing radial glial progenitor cells. With innovative approaches including high-temporal live imaging and molecular genetics techniques, the proposed research will provide fundamental new insights into the molecular and cellular regulation of radial glial progenitor cell division and neocortical neurogenesis. Many human neurological and psychiatric disorders are associated with defects in neocortical neurogenesis, ranging from the severe malformations of mental retardation and epilepsy, to more subtle ones such as autism and maladaptive behavior associated with drug abuse. The results of this application will shed light on the etiology of these disorders.