Control of Shh Activity and Signaling in the Neural Tube

神经管中 Shh 活动和信号传导的控制

• 批准号: 8140658
• 负责人: CHIN CHIANG
• 金额: $ 4.93万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140658
• 关键词: Ablation; Architecture; Ataxia; Autistic Disorder; Biological Process; Brain; Brush Cell; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Choroid Plexus Epithelium; Cytoplasmic Granules; Data; Defect; Development; Disease; Epithelium; Foundations; Generations; Genetic; Glutamates; Goals; Interneurons; Knowledge; Ligands; Link; Lip structure; Maintenance; Maps; Molecular Profiling; Motor; Multipotent Stem Cells; Mus; Neural tube; Neuroglia; Neurons; Pathway interactions; Play; Population; Role; Schizophrenia; Signal Transduction; Slice; Source; Stem cells; Structure of choroid plexus; Telencephalon; Tissues; Ventricular; cell behavior; cell type; cognitive function; excitatory neuron; gain of function; hindbrain; insight; medulloblastoma; mutant; nerve stem cell; nervous system disorder; neuroepithelium; novel; progenitor; public health relevance; relating to nervous system; research study; spatiotemporal

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.

描述（由申请人提供）：小脑对于运动协调至关重要，并且在认知功能中起着重要作用。这些功能的执行严重取决于至少七个神经元亚型和不同神经胶质的相互作用。这些细胞类型源自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，某些大的深小脑核（DCN）神经元以及单极刷子细胞，是由RL产生的。相比之下，VZ是GABA能神经元的主要来源，包括Purkinje神经元，小型DCN神经元和至少5种抑制性中间神经元。尽管了解小脑祖细胞的生日和分化命运，但对调节小脑发育过程中不同神经元亚型身份的规范和扩展的信号的身份和来源知之甚少。在过去的几年中，我们已经产生了SHH肌肌型突变体和远程SHH功能收益突变体。对神经管中这些突变体的分析使我们能够发现SHH在小脑中的先前未欣赏的作用。该提案的目的是填补有关控制小脑祖细胞行为的信号传导机制的关键空白，及其对皮质间神经元结构的贡献。 公共卫生相关性：小脑对于运动协调至关重要，并且在认知功能中起着重要作用。小脑发育的疾病与共济失调，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。