Genetic Analysis of Mouse Nervous System Development

描述（由申请方提供）：小鼠神经管腹侧一半中细胞类型的规格取决于Sonic hedgehog（Shh）信号通路的分级活性。最近的研究结果表明，鞭毛内运输（IFT）蛋白的规格所需的Shh依赖的腹侧神经细胞类型。IFT蛋白是纤毛产生所必需的，纤毛似乎充当细胞对Shh信号做出反应所需的细胞器。遗传和生物化学实验将确定在Smo和Gli蛋白之间起作用的Shh途径的两个组分Sufu和PKA的活性是否取决于纤毛。实验将测试特定的IFT蛋白Dnchc2和IFT 172是否在Hh信号传导中具有独特的功能。遗传实验将测试Dnchc 2是否定义了Hh信号沿着前后体轴的机制差异。生化实验将测试IFFT 172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个信号传导途径所需的，Pdgf和非经典Wnt信号传导，以及纤毛是否作为信号整合的位点。基底体在神经模式形成期间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底体成分的表型来测试。新的ENU突变，影响运动神经元的规格将被表征。由于异常Hh信号传导在出生缺陷和癌症中的重要作用，Hh通路的哺乳动物特异性组分的表征对人类健康具有重要意义。该途径的这些拟南芥特异性组分可能在人类先天性疾病和人类肿瘤中发生突变。这些新的成分还可以为治疗与异常Hh信号传导相关的疾病提供新的药物靶点。最近，大量的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。

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.