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

小鼠胚胎神经干细胞运动核迁移的机制和功能

基本信息

批准号：
10735468
负责人：
Zhigang Xie
金额：
$ 37.68万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735468
关键词：
Apical Brain Cell Cycle Cell Differentiation process Cell Proliferation Data Defect Development Developmental Disabilities Electroporation Embryo Embryonic Development Ensure Equilibrium Event Experimental Designs Gene Silencing Impairment In Vitro Inhibition of Cell Proliferation Knock-out Lead Ligands Link Mediating Mitosis Modeling Morphogenesis Movement Mus Neocortex Neurons Nuclear Organoids Pathogenesis Pathway interactions Plasmids Proliferating Risk Role Shapes Signal Transduction Structure Surface System Testing Thick Tissue Engineering Tissue Expansion Tissues WNT11 gene WNT5A gene autism spectrum disorder autocrine brain cell brain tissue cell behavior conditional knockout convergent extension design experimental study in utero in vivo insight mechanical signal migration neocortical nerve stem cell neurogenesis neuromechanism neuroregulation novel paracrine planar cell polarity risk variant self organization stem cell proliferation

项目摘要

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.

项目总结