Role of Lis1 in Radial and Non-Radial Neural Migration

描述(申请人提供)：中枢神经系统的发育包括大量的细胞从祖细胞带迁移到成年神经元所在的位置。细胞向新皮质迁移有两条途径：径向和非径向。神经元沿径向路径迁移的直接可视化表明，细胞可以通过易位或移动来移动细胞，易位是指引导过程的延伸，随后是细胞核的移动，或者是移动，是细胞核和细胞体作为一个单一单元的移动。神经迁移的异常与许多人类发育障碍有关。LIS-1是一种突变基因，在许多孤立的利脑序列和Miller-Dieker综合征的病例中发生突变，它与新皮质放射状迁移的缺陷有关。鉴于Lis-1在细胞运动中的基础作用，假设Lis-1对于细胞迁移的移动和易位模式都是基本需要的，因此它将是正常的非径向细胞迁移所必需的。要了解LIS-1突变患者的完整表型，需要了解LIS-1‘S功能的方方面面，包括在非放射状迁移中的任何作用。通过使用延时视频显微镜观察胚胎脑片中的放射状迁移，特定的AIMS 1和2将检验假说，即在半合子LIS-1基因敲除小鼠中，通过移位和运动引起的径向迁移和非径向迁移将会较慢。最后，在特定的目标3中，描述了实验来验证LIS-1突变小鼠具有异常的总体非径向迁移模式和异常的非径向迁移的最终定位的假设。这一假设将在LIS-1半合子突变小鼠上使用BrdU出生测年法进行验证，这些突变小鼠在非放射状迁徙中表达EGFP。这些数据将提供有价值的信息，最终将有助于更好地诊断、管理和治疗迁徙障碍患者。

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.