Genetic Analysis of Mouse Nervous System Development

小鼠神经系统发育的遗传分析

• 批准号: 8097941
• 负责人: Kathryn V Anderson
• 金额: $ 40.73万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097941
• 关键词: Affect; Anterior; Biochemical; Carrier Proteins; Cell Nucleus; Cells; Cilia; Congenital Abnormality; Congenital Disorders; Coupled; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Disease; Dorsal; Drug Delivery Systems; Embryo Loss; Employee Strikes; Erinaceidae; Ethylnitrosourea; Eye; Fibroblasts; Genes; Genetic; Grant; Health; Human; Induced Mutation; International; Maintenance; Malignant Neoplasms; Mammalian Cell; Membrane Proteins; Microtubules; Motor; Motor Neurons; Mus; Mutate; Mutation; Neural Tube Closure; Neural tube; Neurons; Oligodendroglia; Organelles; Pathway interactions; Phenotype; Play; Polydactyly; Production; Proteins; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Site; Sonic Hedgehog Pathway; Structure; Syndrome; Testing; base; cell type; design; genetic analysis; hedgehog signal transduction; human SMO protein; kinetosome; molecular marker; mutant; nerve stem cell; nervous system development; neural patterning; neurodevelopment; novel; receptor; relating to nervous system; research study; smoothened signaling pathway; trafficking; transcription factor; tumor

DESCRIPTION (provided by applicant): The specification of cell types in the ventral half of the mouse neural tube depends on graded activity of the Sonic hedgehog (Shh) signaling pathway. Recent results demonstrated that Intraflagellar transport (IFT) proteins are required for the specification of Shh-dependent ventral neural cell types. IFT proteins are required for the production of cilia, and cilia appear to act as organelles that are required for cells to respond to Shh signals. Genetic and biochemical experiments will establish whether the activity of two components of the Shh pathway that act between Smo and Gli proteins, Sufu and PKA, depend on cilia. Experiments will test whether specific IFT proteins, Dnchc2 and IFT172, have unique functions in Hh signaling. Genetic experiments will test whether Dnchc2 defines differences in the mechanism of Hh signaling along the anterior-posterior body axis. Biochemical experiments will test whether IFT172 has a dual function in the cilium and in the nucleus. Experiments will test whether cilia are required for two other signaling pathways important in neural development, Pdgf and non-canonical Wnt signaling, and whether cilia act as sites for signal integration. The hypothesis that the basal body acts as a signaling center during neural patterning will be tested by examining the phenotypes of key basal body components, using existing gene trap mutations. New ENU-mutations that affect the specification of motor neurons will be characterized. Because of the important roles of abnormal Hh signaling in birth defects and cancer, the characterization of mammalian-specific components of the Hh pathway has important implications for human health. These mammalian-specific components of the pathway may be mutated in human congenital disorders and in human tumors. The new components may also provide novel drug targets for treatment of disorders associated with abnormal Hh signaling. A large number of human congenital disorders have recently been connected to defects in cilia. These studies will help define which of the phenotypes associated with these syndromes are the result of inappropriate signaling by the Hh and other signaling pathways.

描述（由申请人提供）：小鼠神经管腹侧半部的细胞类型规格取决于 Sonic Hedgehog (Shh) 信号通路的分级活性。最近的结果表明，鞭毛内转运 (IFT) 蛋白是 Shh 依赖性腹侧神经细胞类型的规范所必需的。 IFT 蛋白是纤毛产生所必需的，而纤毛似乎充当细胞响应 Shh 信号所需的细胞器。遗传和生化实验将确定在 Smo 和 Gli 蛋白之间起作用的 Shh 通路的两个成分（Sufu 和 PKA）的活性是否依赖于纤毛。实验将测试特定的 IFT 蛋白 Dnchc2 和 IFT172 是否在 Hh 信号传导中具有独特的功能。基因实验将测试 Dnchc2 是否定义了沿身体前后轴的 Hh 信号传导机制的差异。生化实验将测试IFT172是否在纤毛和细胞核中具有双重功能。实验将测试纤毛是否是神经发育中重要的另外两种信号通路（Pdgf 和非经典 Wnt 信号传导）所必需的，以及纤毛是否充当信号整合位点。基体在神经模式形成过程中充当信号中心的假设将通过使用现有的基因陷阱突变检查关键基体成分的表型来测试。影响运动神经元规格的新 ENU 突变将得到表征。由于异常 Hh 信号传导在出生缺陷和癌症中的重要作用，Hh 通路哺乳动物特异性成分的表征对人类健康具有重要意义。该途径的这些哺乳动物特异性成分可能在人类先天性疾病和人类肿瘤中发生突变。新成分还可能为治疗与 Hh 信号异常相关的疾病提供新的药物靶点。最近，大量人类先天性疾病与纤毛缺陷有关。这些研究将有助于确定哪些与这些综合征相关的表型是 Hh 和其他信号通路不适当信号传导的结果。