Control of Shh Activity and Signaling in the Neural Tube

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DESCRIPTION (provided by applicant): The cerebellum is essential for motor coordination and plays an important role in cognitive function. The execution of these functions critically depends on interaction among at least seven neuronal subtypes and different glia. These cell types are derived from two separate germinal neuroepithelia: ventricular zone (VZ) and rhombic lip (RL). All glutamatergic neurons including granule neurons, the most abundant neurons in the brain, certain large deep cerebellar nuclei (DCN) neurons as well as unipolar brush cells are generated from the RL. In contrast, VZ is the primary source of GABAergic neurons including Purkinje neurons, small DCN neurons and at least 5 classes of inhibitory interneurons. Despite knowledge of birthdate and differentiation fates of cerebellar progenitors, very little is known about the identity and source of the signals that regulate the specification and expansion of different neuronal subtype identities during cerebellar development. During the past few years, we have generated Shh hypomorphic mutants and long-range Shh gain-of-function mutants. The analysis of these mutants in the neural tube permitted us to uncover a previously unappreciated role of Shh in the cerebellum. The goal of this proposal is to fill critical gaps in our knowledge regarding the signaling mechanism that governs cerebellar progenitor cell behaviors and their contribution to cortical interneuron architecture. PUBLIC HEALTH RELEVANCE: The cerebellum is essential for motor coordination and plays an important role in cognitive function. Disorders of cerebellar development are associated with neurological diseases such as ataxia, autism, schizophrenia and medulloblastoma. Therefore, elucidating the mechanism that regulates the generation and diversification of different kinds of neurons during cerebellar development will provide the foundation for understanding and eventual treatment of these diseases.