Control of Shh Activity and Signaling in the Neural Tube

描述(申请人提供)：小脑是运动协调所必需的，在认知功能中起着重要作用。这些功能的执行关键依赖于至少七种神经元亚型和不同胶质细胞之间的相互作用。这些细胞类型来自两个独立的生发神经上皮：脑室带(VZ)和菱形唇部(RL)。所有的谷氨酸能神经元，包括颗粒神经元、脑中含量最丰富的神经元、某些大的深小脑核(DCN)神经元以及单极刷状细胞都是由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。尽管知道小脑前体细胞的出生日期和分化命运，但对调节小脑发育过程中不同神经元亚型身份的指定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亚型突变体和远程Shh功能增益突变体。对神经管中这些突变体的分析使我们能够揭示Shh在小脑中以前未被认识到的作用。这一建议的目的是填补我们在控制小脑祖细胞行为的信号机制及其对皮质神经元间结构的贡献方面知识的关键空白。 公共卫生相关性：小脑是运动协调的关键，在认知功能中发挥着重要作用。小脑发育障碍与神经疾病有关，如共济失调、自闭症、精神分裂症和髓母细胞瘤。因此，阐明小脑发育过程中不同类型神经元的产生和多样化的调控机制，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.