Neurogenesis and Migration in Developing Cerebral Cortex

描述（由申请人提供）：大脑皮层是大脑结构，是我们最高认知和感知能力的基础。在发育过程中，皮质神经上皮细胞的增殖细胞产生年轻的神经元，这些神经元从它们的起源部位迁移到皮质内的不同位置，从那里它们形成特定的轴突连接。大脑皮层神经元的产生和迁移缺陷对心理健康有着根本性的影响。在患有自闭症的幼儿中观察到大脑皮层的大小增加，并且迁移障碍与精神分裂症、双相情感疾病、癫痫和阅读障碍有关。我们还注意到，已知在X连锁精神发育迟滞中发生突变的基因中，至少有六个涉及利用Rho家族GTP酶的信号通路，这些GTP酶与神经发生和迁移有关。我们研究的目标是确定调节神经发生的分子，确定皮质祖细胞如何决定是否产生神经元或更多的祖细胞，并描述年轻神经元迁移到大脑中适当位置的机制。本文主要研究了以下问题：1）纤毛是如何影响皮质祖细胞的增殖的？我们假设纤毛调节信号系统，控制神经祖细胞的增殖。2)粘附、张力和内吞作用的空间调节如何促进神经元迁移？我们建议可视化迁移神经元和细胞外基质之间的粘附接触的建立，并探讨这些接触逐渐减弱网格蛋白介导的内吞作用的假设。3)Rho家族GTP酶在调节神经祖细胞增殖和年轻神经元迁移中起什么作用？为了探索Rac 1和Cdc42在神经元发育早期阶段的作用，我们建议使用条件遗传学消融Cdc42或Rac 1在发育中的小鼠大脑，并评估这些基因在神经祖细胞增殖和神经元迁移中的作用。 公共卫生相关性：我们正在探索控制大脑皮层神经元产生和迁移的分子机制。在患有自闭症的幼儿中观察到大脑皮层的大小增加，并且迁移障碍与精神分裂症、双相情感疾病、癫痫和阅读障碍有关。我们的研究部分集中在Rho家族GTPases，这与X连锁精神发育迟滞有关。

DESCRIPTION (provided by applicant): The cerebral cortex is the brain structure that underlies our highest cognitive and perceptual abilities. During development, proliferating cells of the cortical neuroepithelium generate young neurons that migrate away from their site of origin into distinct positions within the cortex, from which they form specific axonal connections. Defects in the production and migration of cerebral cortical neurons have fundamental implications for mental health. An increase in the size of the cerebral cortex is observed in young children with autism, and migration disorders have been implicated in schizophrenia, bipolar affective illness, epilepsy, and dyslexia. We also note that of the genes known to be mutated in X-linked mental retardation, at least six involve signaling pathways that utilize Rho family GTPases, which are implicated in neurogenesis and migration. The goals of our research are to identify molecules that regulate neurogenesis, to determine how cortical progenitors decide whether to produce neurons or more progenitors, and to characterize the mechanisms by which young neurons migrate to appropriate positions in the brain. The following questions are addressed: 1) How do cilia influence the proliferation of cortical progenitor cells? We hypothesize that the cilia regulate signaling systems that control the proliferation of neural progenitor cells. 2) How does the spatial regulation of adhesion, tension, and endocytosis contribute to neuronal migration? We propose to visualize the establishment of adhesive contacts between migrating neurons and the extracellular matrix and to explore the hypothesis that these contacts are progressively weakened by clathrin-mediated endocytosis. 3) What role do Rho family GTPases play in regulating neural progenitor proliferation and the migration of young neurons? To explore the roles of Rac1 and Cdc42 at early stages of neuronal development, we propose to use conditional genetics to ablate Cdc42 or Rac1 in the developing mouse brain and to assess the roles of these genes in the proliferation of neural progenitor cells and in neuronal migration. PUBLIC HEALTH RELEVANCE: We are exploring the molecular mechanisms that control the production and migration of neurons in the cerebral cortex. An increase in the size of the cerebral cortex is observed in young children with autism, and migration disorders have been implicated in schizophrenia, bipolar affective illness, epilepsy, and dyslexia. Our studies focus in part on Rho family GTPases, which are implicated in X-linked mental retardation.