9: NOTCH SIGNALING AND SKELETAL MUSCLE FUNCTION

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我实验室工作的长期目标是了解Notch信号通路在哺乳动物胚胎发育过程中发挥的多种作用，以及该通路与先天性人类疾病综合征发展之间的联系。Notch信号通路的组分构成了一组进化上保守的蛋白质，其控制许多组织中的细胞命运特化，并且对于昆虫、线虫和哺乳动物等多种生物体中的适当胚胎发育至关重要。在果蝇中，Notch基因编码一个大的跨膜受体，在细胞的细胞外表面，与Delta和Serrate基因编码的膜结合配体相互作用。在哺乳动物中，已经描述了四种Notch家族受体：Notch 1、2、3和4。已经描述了编码Notch受体家族的配体的五种基因：两种Jagged/Serrate家族（Jag 1和Jag 2）和三种Delta样家族（Dll 1、Dll 3和Dll 4）。虽然先前的工作已经揭示了Notch信号在调节肌发生和骨骼肌卫星细胞活化中的作用，但尚未描述进行性Notch信号依赖性肌病模型。我们已经发现，Notch配体Dll 1和Jag 2突变的双杂合小鼠（Dll 1/Jag 2 +/-小鼠）表现出进行性出生后肌病，优先影响背部的轴上肌肉。该模型为研究Notch信号在哺乳动物骨骼肌功能中的生理作用提供了一个有价值的新资源。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long term goal of the work in my laboratory is to understand the multiple roles that the Notch signaling pathway plays during embryonic development in mammals, and the connections between this pathway and the development of congenital human disease syndromes. The components of the Notch signaling pathway constitute an evolutionarily-conserved set of proteins that controls cell fate specification in numerous tissues, and is essential for proper embryonic development in organisms as diverse as insects, nematodes and mammals. In Drosophila, the Notch gene encodes a large transmembrane receptor that, at the extracellular surface of a cell, interacts with membrane-bound ligands encoded by the Delta and Serrate genes. In mammals, four Notch family receptors have been described: Notch1, 2, 3 and 4. Five genes encoding ligands for the Notch family of receptors have been described: two of the Jagged/Serrate family (Jag1 and Jag2) and three of the Delta-like family (Dll1, Dll3 and Dll4). While previous work has revealed a role for Notch signaling in regulating myogenesis and skeletal muscle satellite cell activation, no progressive Notch signaling-dependent myopathy model has been described. We have found that mice doubly heterozygous for mutations of the Notch ligands Dll1 and Jag2 (Dll1/Jag2 +/- mice) exhibit a progressive postnatal myopathy that preferentially affects epaxial muscles of the back. This model provides a valuable new resource for studying the physiological role of Notch signaling during skeletal muscle function in mammals.