Signaling mechanisms in cerebellar development and function

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DESCRIPTION (provided by applicant): The cerebellum is essential for motor coordination and learning, and it is also implicated in contributing to cognitive function and social learning. Alterations in specific aspects of these functions are associated with various debilitating developmental diseases including ataxia and autism spectrum disorder in humans. The cerebellar circuitry is comprised of limited number of inhibitory and excitatory neurons that are integrated in the corticonuclear network, with Purkinje neurons (PN) being the sole output neurons. Precise assembly of this circuitry which governs cerebellar function is likely dependent on the balanced production of inhibitory and excitatory neurons from their precursors, yet these processes remain poorly understood. During the current funding period, we have shown that the PN is a central regulator of late-born neural precursors in the postnatal cerebellum, coupling the generation of excitatory and inhibitory interneurons and facilitating their coordinated integration into the emerging cerebellar circuit. PN accomplish these crucial tasks through disseminating Sonic hedgehog (Shh) to functionally and spatially distinct neurogenic niches, namely external granule layer and prospective white matter (PWM). Although Shh can travel far from its site of synthesis, the mechanisms remain unknown. The PWM consists of a heterogeneous population of precursors and the function of Shh signaling specifically in inhibitory neuronal precursors needs to be determined. Moreover, Shh-derived from PN also signal to neighboring Bergmann glia (BG), and how such regulation is integrated with the generation of excitatory neurons is also unknown. The goal of this proposal is to fill these critical gaps using a combination of multidisciplinary approaches.