Control of Shh Activity and Signaling in the Neural Tube

描述（申请人提供）：小脑对运动协调至关重要，在认知功能中起着重要作用。这些功能的执行主要取决于至少七种神经元亚型和不同胶质细胞之间的相互作用。这些细胞类型来源于两个独立的生发神经上皮：心室区（VZ）和菱形唇（RL）。所有谷氨酸能神经元，包括颗粒神经元，大脑中最丰富的神经元，某些大深部小脑核（DCN）神经元以及单极刷细胞都是由RL产生的。相比之下，VZ是gaba能神经元的主要来源，包括浦肯野神经元、小DCN神经元和至少5类抑制性中间神经元。尽管对小脑祖细胞的出生日期和分化命运有所了解，但对小脑发育过程中调节不同神经元亚型身份的特征和扩展的信号的身份和来源知之甚少。在过去的几年里，我们已经产生了Shh半胚突变体和远程Shh功能获得突变体。对这些神经管突变体的分析使我们发现了Shh在小脑中以前未被认识到的作用。这一建议的目标是填补我们关于控制小脑祖细胞行为的信号机制及其对皮层神经元间结构的贡献的知识的关键空白。

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.