Non-Radial Cell Migration in CNS Development

中枢神经系统发育中的非径向细胞迁移

• 批准号: 6560609
• 负责人: Jeffrey A Golden
• 金额: $ 28.26万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6560609
• 关键词: axon; cell migration; central nervous system; chick embryo; developmental neurobiology; epilepsy; gene expression; genetically modified animals; glycoproteins; immunocytochemistry; interneurons; laboratory mouse; mental retardation; neuronal guidance; polymerase chain reaction

DESCRIPTION (provided by applicant): Epilepsy, mental retardation and structural anomalies of the brain often have a genetic etiology. Although they affect 3-5% of all children, the underlying pathogeneses for these disorders is poorly understood in most cases. Cell migration is a central component of normal central nervous system (CNS) development and disruptions in this process have been implicated in the development of multiple disorders such as Fukuyama Muscular dystrophy, Miller-Dieker Syndrome, Walker-Warburg Syndrome, and the Muscle-Eye-Brain syndrome to name just a few. Two primary patterns of cell migration are recognized during CNS development, radial and non-radial. While the cellular and molecular bases of radial cell migration, long considered the predominant mode of cell migration, have begun to be defined, the mechanisms of guidance for non-radial cell migration remain largely unexplored. Using lineage analysis, we have defined the developmental time and location where non-radial cell migration begins in the chick forebrain. Based on these data we have developed a model to explain the cellular and molecular mechanisms of non-radial cell migration. Our model is based on the hypotheses that cell surface molecules, secreted molecules, and extracellular matrix molecules guide non-radially migrating cells. This proposal will begin to address our hypothesis by 1) directly testing several components of our model, and 2) generate a mammalian model to further study one of the molecules we have identified as a component of non-radial cell migration in the chick. These data will certainly enhance our understanding of normal CNS development. Furthermore, we anticipate the data from these studies will provide insight into the pathogenesis of a variety of inherited and non-inherited conditions that afflict children such as epilepsy, mental retardation and structural malformations of the brain. This may ultimately lead to improvements in the diagnosis, management, and prevention of neurological diseases where abnormal cell migration has a pathogenetic role.

描述（由申请人提供）：癫痫、智力迟钝和大脑结构异常通常具有遗传病因。虽然它们影响所有儿童的3-5%，但在大多数情况下，对这些疾病的潜在病因知之甚少。细胞迁移是正常中枢神经系统（CNS）发育的核心组成部分，并且该过程中的破坏已经涉及多种病症的发展，例如福山肌营养不良、米勒-迪克尔综合征、沃克-沃伯格综合征和肌-眼-脑综合征，仅举几例。在中枢神经系统发育过程中，细胞迁移的两种主要模式是放射状和非放射状。虽然放射状细胞迁移的细胞和分子基础，长期以来被认为是细胞迁移的主要模式，已经开始被定义，非放射状细胞迁移的指导机制仍然在很大程度上未被探索。使用谱系分析，我们已经定义了发育的时间和位置，非放射状细胞迁移开始在鸡前脑。基于这些数据，我们已经开发了一个模型来解释非径向细胞迁移的细胞和分子机制。我们的模型是基于假设，细胞表面分子，分泌的分子，和细胞外基质分子引导非径向迁移的细胞。该提议将通过以下方式开始解决我们的假设：1）直接测试我们模型的几个组件，以及2）生成哺乳动物模型以进一步研究我们已鉴定为鸡中非放射状细胞迁移组件的分子之一。这些数据肯定会增强我们对正常CNS发育的理解。此外，我们预计这些研究的数据将提供深入了解各种遗传和非遗传性疾病的发病机制，这些疾病困扰着儿童，如癫痫，精神发育迟滞和大脑结构畸形。这可能最终导致神经系统疾病的诊断，管理和预防的改善，其中异常细胞迁移具有致病作用。