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.