Role of Lis1 in Radial and Non-Radial Neural Migration

描述（由申请人提供）：中枢神经系统的发育涉及广泛的细胞从祖细胞区迁移到成人神经元所在的位置。细胞向新皮层迁移的两种途径已被描述：径向和非径向。神经元沿径向路径的直接可视化表明，细胞可以通过易位，即细胞核运动后的一个主导过程的延伸，或通过运动，即细胞核和细胞体作为一个整体一起运动。神经迁移异常与许多人类发育障碍有关。Lis-1是一种在许多分离性缺脑症和米勒-迪克综合征病例中发生突变的基因，它与新皮层的径向迁移缺陷有关。鉴于Lis-1在细胞运动中的基本作用，我们假设Lis-1在细胞迁移的运动和移位模式中都是必需的，因此它将是正常的非径向细胞迁移所必需的。了解Lis-1突变患者的完整表型需要了解Lis-1功能的各个方面，包括其在非径向迁移中的作用。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径向迁移，验证半合子Lis-1基因敲除小鼠的径向迁移和非径向迁移（易位和运动）速度较慢的假设。最后，在Specific Aim 3中，我们描述了实验来验证Lis-1突变小鼠非径向迁移总体模式异常和非径向迁移最终定位异常的假设。这一假设将在非径向迁移表达eGFP的Lis-1半合子突变小鼠上进行BrdU出生测定。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.