Molecular Control of Progenitor Cell Polarity and Cortical Neurogenesis

描述（由申请人提供）：大脑皮层的正确形成取决于胚胎发育期间大量神经元的有序产生。最近的研究令人信服地表明，放射状胶质细胞是发育中的皮质神经元祖细胞的主要群体。除了它们在引导新生神经元的径向迁移中的充分表征的作用之外，径向胶质细胞在心室区中分裂以产生神经元。在发育中的皮层中精确控制放射状胶质细胞分裂可能是控制成熟大脑皮层中神经元数量的主要因素。尽管在皮质发育中起着重要作用，但调节放射状胶质细胞分裂的机制仍知之甚少。本项目的长期目标是阐明放射状胶质细胞分裂和子细胞命运特化的分子和细胞过程。在神经发生高峰期，放射状胶质细胞主要进行不对称分裂，以自我更新和产生神经元。不对称细胞分裂通常需要分裂细胞被极化，以确保两个子细胞对细胞命运决定子的差异遗传。本提案的目的是揭示放射状胶质细胞极性的分子控制，并定义放射状胶质细胞的极化如何调节其分裂模式（即对称或不对称）在发育中的皮质。放射状胶质细胞起源于上皮细胞，其高度极化，具有不同的顶端和基底亚细胞区室。这种顶基极性由一组进化上保守的蛋白质复合物控制，其中Par（分区缺陷）蛋白质复合物起着核心作用。此外，Par蛋白复合物对于极化果蝇神经系统中的神经祖细胞（即成神经细胞和感觉器官前体，SOP）和确保它们的不对称细胞分裂是必需的。基于这些观察，本申请的中心假设是哺乳动物Par（mPar）蛋白复合物控制发育中皮质中放射状胶质细胞的极性和分裂模式。在强有力的初步数据的指导下，这一假设将通过追求以下三个具体目标来检验：1）确定mPar蛋白复合物在分裂的放射状胶质细胞中的亚细胞定位; 2）确定mPar蛋白复合物在调节放射状胶质细胞分裂和子细胞命运特化中的功能;（3）阐明mPar蛋白复合物在发育中大脑皮层的分子和细胞通路。这种方法是创新的，因为它结合了先进的激光扫描显微镜和分子遗传学技术。这项拟议中的研究将提供关于发育中的皮层中的神经元祖细胞如何分裂产生神经元的新见解。许多人类神经和精神疾病与皮质神经发生的缺陷有关，范围从精神发育迟滞和癫痫的严重畸形到更微妙的疾病，如自闭症和与药物滥用有关的适应不良行为。这项研究的结果可能揭示了许多这些疾病的病因相关的机制。 公共卫生相关性：本研究探讨了神经元祖细胞如何在发育中的大脑中分裂产生神经元的潜在过程，这是神经科学中一个重要且未充分研究的领域。它将推进和扩大对由大脑皮层发育缺陷引起的各种神经和精神障碍的理解和治疗，如精神发育迟滞、癫痫、自闭症和与药物滥用相关的适应不良决策行为。

DESCRIPTION (provided by applicant): Proper formation of the cerebral cortex depends on an orderly production of a large number of neurons during embryonic development. Recent studies have convincingly shown that radial glial cells are a major population of neuronal progenitor cells in the developing cortex. In addition to their well-characterized role in guiding radial migration of newly born neurons, radial glial cells divide in the ventricular zone to generate neurons. Precise control of radial glial cell division in the developing cortex is likely a major factor in controlling the number of neurons in the mature cerebral cortex. Despite this fundamental role in cortical development, the mechanisms that regulate radial glial cell division are poorly understood. The long-term goal of this project is to elucidate the molecular and cellular processes underlying radial glial cell division and daughter cell fate specification. During peak neurogenesis, radial glial cells predominantly divide asymmetrically to self-renew and to generate neurons. Asymmetric cell division usually requires the dividing cells to be polarized so as to ensure differential inheritance of cell fate determinants by the two daughter cells. The objectives of this proposal are to uncover the molecular control of radial glial cell polarity and to define how the polarization of radial glial cells may regulate the mode of their division (i.e. being symmetric or asymmetric) in the developing cortex. Radial glial cells originate from epithelial cells that are highly polarized with distinct apical and basal subcellular compartments. This apical-basal polarity is controlled by a set of evolutionarily conserved protein complexes, among which the Par (partition defective) protein complex plays a central role. Moreover, the Par protein complex is essential for polarizing neural progenitor cells (i.e. neuroblasts and sensory organ precursors, SOPs) in the Drosophila nervous system and ensuring their asymmetric cell division. Based on these observations, the central hypothesis of this application is that the mammalian Par (mPar) protein complex controls the polarity and the division mode of radial glial cells in the developing cortex. Guided by strong preliminary data, this hypothesis will be tested by pursuing these three specific aims: 1) To determine the subcellular localization of the mPar protein complex in dividing radial glial cells; 2) To define the function of the mPar protein complex in regulating radial glial cell division and daughter cell fate specification; and 3) To delineate the molecular and cellular pathways of the mPar protein complex in the developing cortex. The approach is innovative, because it combines advanced laser scanning microscopy with molecular genetics techniques. The proposed research will provide new insights concerning how neuronal progenitor cells in the developing cortex divide to give rise to neurons. Many human neurological and psychiatric disorders are associated with defects in cortical neurogenesis, ranging from severe malformations with mental retardation and epilepsy, to more subtle ones such as autism and maladaptive behavior associated with drug abuse. The results of this study may shed light on mechanisms relevant to the etiology of many of these disorders. PUBLIC HEALTH RELEVANCE: This study investigates the processes underlying how neuronal progenitor cells divide to give rise to neurons in the developing brain, an important and under-investigated area in neuroscience. It will advance and expand the understanding and treatment of a variety of neurological and psychiatric disorders caused through defects in cerebral cortex development, such as mental retardation, epilepsy, autism, and maladaptive decision- making behavior associated with drug abuse.