Role of Lis1 in Radial and Non-Radial Neural Migration

Lis1 在径向和非径向神经迁移中的作用

• 批准号: 6830187
• 负责人: Ilya M Nasrallah
• 金额: $ 1.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830187
• 关键词: Role; Lis1; Radial; Non; Neural

DESCRIPTION (provided by applicant): Central nervous system development involves extensive cellular migration from progenitor zones to the locations where neurons reside in the adult. Two pathways of cell migration to the neocortex have been described: radial and non-radial. Direct visualization of neuronal migration along the radial pathway indicates that cells can move by translocation, the extension of a leading process followed by movement of the nucleus, or by locomotion, the movement of the nucleus and the cell body together as a single unit. Abnormalities in neural migration have been linked to a number of human developmental disorders. Lis-1, a gene mutated in many cases of Isolated Lissencephaly Sequence and Miller-Dieker Syndrome, has been associated with a defect in radial migration in the neocortex. Given the fundamental role for Lis-1 in cell movement, it is hypothesized that Lis-1 is fundamentally required for both the locomotion and translocation modes of cell migration and therefore that it will be required for normal non-radial cell migration. Understanding the complete phenotype of patients with Lis-1 mutations will require understanding all aspects of Lis-1's function, including any role in non-radial migration. Specific Aims 1 and 2 will test the hypotheses, that radial migration and non-radial migration by both translocation and locomotion will be slower in hemizygous Lis-1 knockout mice by using time-lapse video microscopy to observe radial migrants in embryonic brain slices. Finally in Specific Aim 3, experiments are described to test the hypothesis that Lis-1 mutant mice have an abnormal overall pattern of nonradial migration and an abnormal final localization of non-radial migrants. This hypothesis will be tested using BrdU birthdating on Lis-1 hemizygous mutant mice that express eGFP in non-radial migrants. These data will provide valuable information that will ultimately help lead to better diagnosis, management, and treatment for patients with disorders of migration.

描述（由申请人提供）：中枢神经系统发育涉及从祖细胞区域到神经元驻留在成年人的位置的广泛细胞迁移。已经描述了细胞迁移到新皮层的两种途径：径向和非radial。神经元迁移沿径向途径的直接可视化表明，细胞可以通过易位，领先过程的延伸，然后是核的运动，或通过运动，将细胞核和细胞体的运动一起作为单个单元一起移动。神经迁移的异常与许多人类发育障碍有关。 LIS-1是在许多分离的Lissencephaly序列和Miller-Dieker综合征中突变的基因，与新皮层径向迁移的缺陷有关。鉴于LIS-1在细胞运动中的基本作用，假设LIS-1从根本上是细胞迁移的运动和易位模式所必需的，因此对于正常的非放射性细胞迁移是必需的。了解LIS-1突变患者的完整表型将需要了解LIS-1功能的各个方面，包括在非主迁移中的任何作用。具体目的1和2将检验假设，易位和移动的径向迁移和非rad式迁移将在半合子LIS-1敲除小鼠中使用延时视频显微镜观察胚胎脑切片中的径向移民。最后，在特定的目标3中，描述了实验来检验LIS-1突变小鼠具有异常的非自由迁移迁移的总体模式和非主要移民最终定位的假设。该假设将使用BRDU在非属性移民中表达EGFP的LIS-1半合子突变小鼠上进行检验。这些数据将提供有价值的信息，最终将有助于为迁移障碍患者提供更好的诊断，管理和治疗。