Role of Lis1 in Radial and Non-Radial Neural Migration

描述（由申请人提供）：中枢神经系统发育涉及从祖细胞区到成人神经元所在位置的广泛细胞迁移。已经描述了细胞迁移到新皮质的两种途径：径向和非径向。神经元沿着放射状通路沿着迁移的直接可视化表明，细胞可以通过移位（引导过程的延伸，随后是细胞核的移动）或通过运动（细胞核和细胞体作为一个单一单元一起移动）来移动。神经迁移的异常与许多人类发育障碍有关。Lis-1是一种在许多孤立性无脑序列和Miller-Dieker综合征病例中发生突变的基因，与新皮质放射状迁移缺陷相关。考虑到Lis-1在细胞运动中的基本作用，假设Lis-1是细胞迁移的运动和易位模式所必需的，因此它将是正常非放射状细胞迁移所必需的。要了解Lis-1突变患者的完整表型，需要了解Lis-1功能的所有方面，包括在非径向迁移中的任何作用。具体目标1和2将通过使用延时视频显微镜观察胚胎脑切片中的放射状迁移物来检验假设，即在半合子Lis-1敲除小鼠中，通过移位和运动的放射状迁移和非放射状迁移将较慢。最后，在具体目标3中，描述了实验以检验Lis-1突变小鼠具有异常的非放射状迁移的总体模式和异常的非放射状迁移者的最终定位的假设。将使用BrdU出生日期对在非放射状迁移者中表达eGFP的Lis-1半合子突变小鼠测试该假设。这些数据将提供有价值的信息，最终有助于更好地诊断、管理和治疗迁移性疾病患者。

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.