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.

项目摘要研究神经干细胞（NSC）如何在发育中的大脑中增殖，分化和自组织体内将导致对发育障碍的发病机理更好地理解，并可能提供关于体外脑器官培养的设计的重要指导。而NSC增殖的机制和分化已经进行了深入研究，NSC在大脑过程中如何在空间上进行自我组织形态发生在很大程度上尚未探索。在此应用中，胚胎鼠标新皮层用于在体内研究NSC空间组织。在胚胎开发过程中，新皮层内的NSC经历在神经发生发作之前，组织内表面（即顶端表面）的有丝分裂。 NSC池的扩增与新皮层的快速外向扩张一致。机制内表面的哪些有丝分裂被转化为组织的外部膨胀，在很大程度上不清楚。一个 PI的最新研究表明，NSCS的标志性特征，Interetic核迁移（IKNM），通过收敛扩展机制促进新皮层扩张。基于这项研究和其他初步数据，在此应用中提出了三个特定目标，以阐明该机制平面细胞极性（PCP）信号传导调节IKNM和新皮质形态发生。在目标中，实验是提议测试PCP信号调节IKN和新皮质的两个竞争模型形态发生。在AIM B中，实验旨在检验以下假设：PCP信号保持通过抑制YAP1/TAZ的核定位，IKNM和细胞增殖的平衡，这是Master 河马信号传导和机械提示下游细胞增殖的调节剂。在AIM C中，自闭症的作用将检查IKNM依赖性新皮质形态发生中的风险基因。该申请将带来专业严重研究领域的进步，即新皮质形态发生过程中NSC空间组织。从本应用程序中发现的关于NSC空间组织的基本原则可能会提供关于脑器官体外培养策略的重要指南，并将自闭症风险基因与调节联系起来在新皮质发展的早期阶段，NSC空间组织