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.
