Mechanisms of Purkinje cell migration

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 DESCRIPTION (provided by applicant): The cerebellum coordinates and synchronizes balance, movement, emotion and cognition. Cerebellar defects contribute to disorders in motor control, equilibrium, posture and learning and are frequent pathological signs in epilepsy and autism. The seeming simplicity of cerebellar structure belies its developmental complexity, with reciprocal interactions between the two principal cell types, the Purkinje cells and granule cells. The resulting cell non-autonomous effects have been an obstacle to understanding the developmental mechanisms. The textbook view has been that Purkinje cells migrate by locomotion along radial glia fibers, and absence of an environmental cue, Reelin, inhibits detachment from the radial glia. However, there are reasons to question this view. First, Purkinje cells were recently seen to move across rather than along radial glia. Second, even though Reelin regulates neuron migrations in the forebrain, it regulates glia-independent migration. In addition, we recently found that an E3 ubiquitin ligase, CRL5, regulates Purkinje cell migration, but, again, the cellular mechanism is unknown. These issues are currently difficult to address because it is challenging to genetically manipulate individual Purkinje cells and observe their migrations in a normal environment. Therefore, our immediate goal is to adapt methods to track and genetically alter Purkinje cells as they migrate and differentiate in the cerebellum. Then, we will combine these new methods with our experience studying neuron migration in the neocortex in order to address key questions of how Purkinje cells migrate and how they are regulated by Reelin and CRL5. An ancillary benefit of the proposed research is that the methods we develop will be invaluable for future investigation of pre- and post-natal cerebellar development, disease and degeneration.