Regulation Of Cortical Neurogenesis By Apical Complex Proteins

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DESCRIPTION (provided by applicant): Normal development of the cerebral cortex depends upon the successful control of proliferation and differentiation of cortical progenitor cells, which is tightly orchestrated by cellular and molecular events that balance the generation of early-born neurons with the maintenance of progenitors for later-born neurons. When this crucial developmental process does not occur properly, abnormalities in the cortical structure are a result, often leading to developmental disabilities such as mental retardation, epilepsy, and autism. Recent studies have shown that the function of apical complex proteins is important in maintaining the progenitor fate. Pals1 is a scaffolding protein and a central component of apical complex proteins in the neural progenitor cells. To delineate the molecular mechanisms that control progenitor proliferation by apical complex proteins, Pals1 conditional knockout mouse model was generated. Loss of Pals1 causes defects in self-renewal of neural epithelial progenitors, leading to their exit of the cell cycle prematurely. The cell fate changes seen in the Pals1-deficient mice are accompanied by aberrant distribution of apical complex proteins and adherens junction (AJ) proteins, and disrupted membrane structure. Based on these observations, we hypothesize that Pals1 orchestrates the control of neural progenitor proliferation and the ultimate fate of cells in the cerebral cortex by regulating membrane architecture and cell polarity through interaction with apical complex proteins and AJ components. To test this hypothesis, the function of Pals1 in cell fate decision of radial glia progenitors (RGPs), which generate the majority of neurons, will be examined. The direct function of Pals1 in the cell fate will be determined by characterizing the cell fate changes elicited by Pals1 loss in the RGPs, and by analyzing the changes in the polarized shape and distribution of proteins. To determine the Pals1 distribution and function in mitosis, we will examine the dynamics of Pals1 distribution during mitosis and follow the fate of daughter cells, depending on Pals1 inheritance or changes in subcellular localization of Pals1; and define the Pals1 function in progenitor division by analyzing the mitosis defects of Pals1-deficient RGPs through time-lapse imaging. Lastly, to delineate the molecular pathways that underlie Pals1 function of cell fate decision, we will examine the Pals1 function in regulating the formation of adhesive cell-cell junction by the assembly of the apical complex, and targeting of cadherins to AJ and the lateral cell junction. We will also explore the Pals1 function in establishment of local signaling(s) that is essential for cell fate decision by interaction with the Par complex. The results of this study will provide valuable information regarding how proliferation control of neural progenitor cells is regulated during normal development, and may lead to important insights about the mechanisms causing devastating neurodevelopmental disorders. PUBLIC HEALTH RELEVANCE: Abnormalities in the development of cerebral cortex often cause devastating neurological disorders such as mental retardation, autism and epilepsy. The studies of molecular mechanisms that control neural progenitor proliferation will provide not only the better understanding of normal development of cerebral cortex, but also knowledge about disease causing mechanism that may lead to the potential therapeutics and possible prevention in the future.