Control of Shh Activity and Signaling in the Neural Tube

描述（由申请人提供）：小脑对运动协调至关重要，在认知功能中起着重要作用。这些功能的执行关键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殖神经上皮细胞：心室区（VZ）和菱形唇（RL）。所有的海马能神经元，包括颗粒神经元，大脑中最丰富的神经元，某些大的小脑深核（DCN）神经元以及单极刷细胞都是从RL产生的。相反，VZ是GABA能神经元的主要来源，包括Purkinje神经元、小DCN神经元和至少5类抑制性中间神经元。尽管小脑祖细胞的出生日期和分化命运的知识，很少有人知道的身份和来源的信号，调节规格和扩展不同的神经元亚型身份在小脑发育。在过去的几年中，我们已经产生了Shh亚纯型突变体和长距离Shh功能获得突变体。对神经管中这些突变体的分析使我们能够揭示Shh在小脑中的一个以前未被重视的作用。这个建议的目标是填补关键的差距，我们的知识有关的信号传导机制，控制小脑祖细胞的行为和他们的贡献，皮层中间神经元的架构。 公共卫生相关性：小脑对运动协调至关重要，在认知功能中起着重要作用。小脑发育障碍与共济失调、自闭症、精神分裂症和髓母细胞瘤等神经系统疾病有关。因此，阐明在小脑发育过程中调节不同类型神经元的产生和多样化的机制将为理解和最终治疗这些疾病提供基础。

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.