Signaling mechanisms in cerebellar development and function

描述（申请人提供）：小脑对运动协调和学习至关重要，也涉及认知功能和社会学习。这些功能特定方面的改变与各种衰弱性发育疾病有关，包括人类共济失调和自闭症谱系障碍。小脑回路由有限数量的抑制和兴奋神经元组成，这些神经元整合在皮质核网络中，浦肯野神经元（PN）是唯一的输出神经元。这种控制小脑功能的电路的精确组装可能依赖于抑制和兴奋神经元从其前体的平衡生产，但这些过程仍然知之甚少。在目前的资助期内，我们已经证明PN是出生后小脑中出生晚的神经前体的中枢调节器，耦合兴奋性和抑制性中间神经元的产生，并促进它们的协调整合

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.