MOLECULAR MECHANISMS OF NEOCORTICAL DEVELOPMENT

新皮质发育的分子机制

• 批准号: 6394486
• 负责人: JANICE E BRUNSTROM
• 金额: $ 23.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394486
• 关键词: biological signal transduction; cell differentiation; cell migration; cellular pathology; confocal scanning microscopy; cyclin dependent kinase; developmental neurobiology; embryogenesis; epilepsy; gamma aminobutyrate; gene targeting; genetically modified animals; immunocytochemistry; laboratory mouse; molecular pathology; neocortex; neural plate /tube; neurogenesis; neurons; neurotrophic factors; phenotype; tissue /cell culture

DESCRIPTION (adapted from applicant's abstract): Abnormalities of human cortical development are a major cause of mental retardation and epilepsy. Lamination of the neocortex depends on crucial early steps, including migration of the earliest cortical plate (CP) neurons that split the preplate and form the marginal zone (MZ) and subplate (SP). Neurotrophin-4 (NT4) causes a large excess of neurons to migrate into the embryonic cortical MZ, in vivo and in vitro, forming heterotopias that distort the underlying CP. These excess neurons share the birthdate and phenotype of subpial granular layer (SGL) neurons of the MZ. Post-natally, animals exposed in utero to NT4 have a second type of CP heterotopia that appears to be caused by the abnormally abundant processes of MZ neurons; these animals have recurrent seizures and die. The goals of this proposal are i) determine the mechanisms that distinguish early and late CP Formation; ii) determine the role of NT4 during normal MZ development, and iii) determine how the T4-induced CP heterotopias form. The specific aims are 1) Determine the mechanisms of radial migration in neocortex: Test the hypotheses that a) neurons destined to split the preplate and form the earliest CP (layer 6), l translocate their cell bodies in a non-glial-guided mechanism that is reelin-dependent, but cdk5/ II 35 independent, and b) neurons, destined for layers 5 and above, migrate via glial-guided mechanisms that are both reelin and cdkS/p35 dependent. 2) Test the hypothesis that the number and phenotype of SGL neurons in the MZ are regulated by NT4 and TrkB. 3) Test the hypothesis that NT4 induces SGL neurons to migrate into the MZ from the retrobulbar "waiting area" and developing striatum 4) Determine the evolution of postnatal CP heterotopias by testing the hypothesis that NT4-induced CP heterotopias form because large groups of cortical neurons are surrounded by aberrantly positioned MZ neurons and their extensive processes. These results suggest that excess production of (or hypersensitivity to) NT4 during early cortical development may play a role in the pathogenesis of human FCDs, and that certain FCDs may arise as a primary disturbance in the development of MZ neurons, secondarily affecting the architecture of subsequent cortical layers. This model should be a valuable tool for identifying the mechanisms underlying the epileptogenicity of dysplastic cortex.

描述（改编自申请人的摘要）：人类异常 皮质发育是造成智力低下和癫痫病的主要原因。 新皮层的层压取决于关键的早期步骤，包括迁移 最早的皮质板（CP）神经元，该神经元将预板和形式分裂 边缘区（MZ）和子板（SP）。 Neurotrophin-4（NT4）导致大型 过多的神经元迁移到胚胎皮质MZ，体内和 体外，形成畸形的异位症，扭曲了基础CP。这些过剩 神经元共享亚皮颗粒层（SGL）的生日和表型 MZ的神经元。在纳塔原来，在子宫内暴露于NT4的动物有第二个 似乎由异常丰富引起的CP异位症的类型 MZ神经元的过程；这些动物复发癫痫发作并死亡。这 该提议的目标是i）确定早期区分的机制 和晚期CP组； ii）确定NT4在正常MZ中的作用 开发，以及iii）确定T4诱导的CP异位肌的形式。这 具体目的是1）确定新皮层中径向迁移的机制： 测试a）神经元注定要拆分预元并形成的假设 最早的CP（第6层），在非胶质引导中转移其细胞体 依赖依赖的机制，但CDK5/ II 35独立，B） 致力于5层及以上的神经元通过神经胶质引导的机制迁移 既取决于reelin and cdks/p35。 2）检验以下假设 MZ中SGL神经元的数量和表型由NT4和TRKB调节。 3） 检验NT4诱导SGL神经元从 后侧面的“等待区”和发展纹状体4）确定 通过检验以下假设的产后CP异位症的演变 NT4诱导的CP异构症形式是因为大量的皮质神经元是 被异常定位的MZ神经元及其广泛的过程包围。 这些结果表明（或过敏）NT4过多产生 在早期皮质发育期间，可能在人类的发病机理中发挥作用 FCD，某些FCD可能是作为主要干扰 MZ神经元的开发，其次影响随后的结构 皮质层。该模型应该是确定的宝贵工具 发育不良皮质的癫痫发作的基础机制。