Mechanism and function of interkinetic nuclear migration in mouse embryonic neural stem cells

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PROJECT SUMMARY Investigating how neural stem cells (NSCs) proliferate, differentiate, and self-organize in the developing brain in vivo will lead to better understanding of pathogenesis of developmental disabilities, and may provide important guidance on the design of in vitro brain organoid culture. While the mechanisms of NSC proliferation and differentiation have been intensively studied, how NSCs spatially self-organize during brain morphogenesis remains largely unexplored. In this application, the embryonic mouse neocortex is used for studying NSC spatial organization in vivo. During embryonic development, NSCs within the neocortex undergo mitosis at the inner surface (i.e. apical surface) of the tissue to self-expand before the onset of neurogenesis. The amplification of the NSC pool coincides with rapid outward expansion of the neocortex. Mechanisms by which mitosis at the inner surface is converted into outward expansion of the tissue remain largely unclear. A recent study from the PI suggests that interkinetic nuclear migration (IKNM), a hallmark feature of NSCs, promotes neocortical expansion via a convergent extension mechanism. Based on this study and additional preliminary data, three Specific Aims are proposed in this application to elucidate the mechanisms by which planar cell polarity (PCP) signaling regulates IKNM and neocortical morphogenesis. In Aim A, experiments are proposed to test two competing models by which PCP signaling regulates IKNM and neocortical morphogenesis. In Aim B, experiments are designed to test the hypothesis that PCP signaling maintains the balance of IKNM and cell proliferation by inhibiting nuclear localization of YAP1/TAZ, which are master regulators of cell proliferation downstream of Hippo signaling and mechanical cues. In Aim C, the role of autism risk genes in IKNM-dependent neocortical morphogenesis will be examined. This application will bring major advancement in a severely understudied field, i.e. NSC spatial organization during neocortical morphogenesis. The basic principles governing NSC spatial organization discovered from this application may provide important guidance on strategies for in vitro culture of brain organoids, and link autism risk genes to regulation of NSC spatial organization during early stages of neocortical development.