Molecular and Cellular Mechanisms of Neocortical Neurogenesis

描述(申请人提供)：新皮质的正确形成依赖于胚胎发育过程中大量神经元的有序产生。放射状胶质细胞已被证明是发育中的新皮质中神经前体细胞的主要群体。除了在引导新生神经元的径向迁移方面发挥了很好的作用外，放射状胶质细胞还在脑室区域分裂生成神经元。对放射状胶质细胞分裂的精确控制决定了成熟新皮质中神经元的数量。尽管在新皮质发育中起着重要作用，但调节放射状神经胶质前体细胞分裂的机制却知之甚少。该项目的长期目标是阐明放射状神经胶质前体细胞分裂的分子和细胞过程。 新皮质神经发生。一般认为，放射状胶质前体细胞最初对称分裂以扩大自身，然后不对称分裂以自我更新并产生新皮质神经元。一种流行的祖细胞不对称分裂模型认为，有丝分裂纺锤体相对于祖细胞极性轴的适当取向确保了关键细胞命运决定因素在两个子细胞之间的不平等分离。我们实验室和其他实验室最近的研究表明，进化上保守的分配缺陷(PAR)蛋白复合体调节放射状神经胶质前体细胞的对称和不对称分裂。此外，我们最近发现，在不对称分裂的放射状胶质前体细胞中复制的母子中心体是由两个子细胞不同地遗传的，这取决于中心体成熟和子细胞命运的指定。作为动物细胞中主要的微管组织中心，中心体不仅对有丝分裂纺锤体的形成至关重要，而且对纤毛的形成也是必不可少的。纤毛是细胞的触角，协调与细胞增殖和分化相关的重要信号通路。基于这些观察，这一应用的中心假设是PAR极性复合体调节有丝分裂纺锤体的方向，母子中心体遗传，以及放射状胶质前体细胞的纤毛发生。在强有力的初步数据的指导下，我们将通过研究mPar蛋白复合体在以下方面的调控功能来验证这一假说：1)有丝分裂纺锤体方向对放射状神经胶质前体细胞的分裂；2)母子中心体遗传对放射状神经胶质前体细胞分裂的影响；3)纤毛发生对放射状神经胶质前体细胞分裂的调节作用。创新的方法包括 通过高时间实时成像和分子遗传学技术，这项拟议的研究将为放射状神经胶质前体细胞分裂和新皮质神经发生的分子和细胞调控提供基本的新见解。许多人类神经和精神障碍与新皮质神经发生缺陷有关，从严重的智力低下和癫痫畸形，到与药物滥用相关的自闭症和适应不良行为等更微妙的畸形。这项应用的结果将有助于阐明这些疾病的病因。

DESCRIPTION (provided by applicant): Proper formation of the neocortex depends on the orderly production of a large number of neurons during embryonic development. Radial glial cells have been demonstrated to be a major population of neuronal progenitor cells in the developing neocortex. In addition to their well-characterized role in guiding radial migration of new-born neurons, radial glial cells divide in the ventricular zone to generate neurons. Precise control of radial glial cell division determines the number of neurons in the mature neocortex. Despite this fundamental role in neocortical development, the mechanisms that regulate radial glial progenitor cell division are poorly understood. The long-term goal of this project is to elucidate the molecular and cellular processes underlying radial glial progenitor cell division and neocortical neurogenesis. It is generally thought that radial glial progenitor cells initially divie symmetrically to amplify themselves and then divide asymmetrically to self- renew and give rise to neocortical neurons. A prevailing model of progenitor cell asymmetric division holds that proper orientation of the mitotic spindle relative to the axis of progenitor cell polarity ensures unequal segregation of critical cellular fate determinants between the two daughter cells. Recent studies from our lab and others have shown that the evolutionarily conserved partition defective (Par) protein complex regulates the symmetric versus asymmetric division of radial glial progenitor cells. Furthermore, we recently found that the duplicated mother and daughter centrosomes in asymmetrically dividing radial glial progenitor cells are differentially inherited b the two daughter cells dependent on the centrosome maturity and daughter cell fate specification. As the major microtubule-organizing center in animal cells, the centrosome is not only critical for the formation of the mitotic spindle, but also absolutely required for the formaton of a cilium, the cellular antennae that orchestrate important signaling pathways related to cell proliferation and differentiation. Based on these observations, the central hypothesis of this application is that the Par polarity complex regulates mitotic spindle orientation, mother versus daughter centrosome inheritance, and ciliogenesis in radial glial progenitor cells. Guided by strong preliminary data, this hypothesis will be tested by investigating the functions of the mPar protein complex in regulating: 1) mitotic spindle orientation in dividing radial glial progenitor cells, 2) mother versus daughter centrosome inheritance in dividing radial glial progenitor cells, and 3) ciliogenesis in dividing radial glial progenitor cells. With innovative approaches including high-temporal live imaging and molecular genetics techniques, the proposed research will provide fundamental new insights into the molecular and cellular regulation of radial glial progenitor cell division and neocortical neurogenesis. Many human neurological and psychiatric disorders are associated with defects in neocortical neurogenesis, ranging from the severe malformations of mental retardation and epilepsy, to more subtle ones such as autism and maladaptive behavior associated with drug abuse. The results of this application will shed light on the etiology of these disorders.