Muscle and Muscle Connective Tissue Development in the Vertebrate Llmb

描述（由申请人提供）：脊椎动物肌肉骨骼系统的发展需要肌肉、肌肉结缔组织、肌腱和骨骼的协调形态发生。在肢体中，肌肉起源于起源于体体的迁移前体，而肌肉结缔组织、肌腱和骨骼成分则起源于起源于侧板的新兴肢芽的中胚层。当肌肉前体迁移到肢体时，它们必须分化成肌纤维，正确地形成独特的解剖肌肉，并组装成功能性的肌肉骨架。40多个肢体肌肉如何形成模式，肌肉和肌肉结缔组织形态发生如何协调是本提案的主题。经典研究表明，侧板、肢体中胚层信号是重要的模式肌。然而，这种信号的分子性质和产生它的组织都不为人所知。最近，我们发现了一群表达转录因子Tcf4的侧板、肢体中胚层细胞，Tcf4是Wnt/ β -连环蛋白信号通路的下游效应因子，对肌肉模式至关重要。小鸡的功能研究表明，表达tcf4的细胞在肢体中胚层建立了一种前模式，这种前模式决定了肌肉前体分化的位置，从而决定了单个肌肉的形成位置和最终的肢体肌肉模式。此外，初步研究表明，表达tcf4的细胞是肌肉结缔组织的前体，而肌肉结缔组织是对肌肉骨骼的形态和功能至关重要的组织，由于缺乏早期分子标记，其发育在很大程度上未被研究。我们建议在小鼠中进行肢体中胚层Tcf4-表达细胞和Wnt/ β -连环蛋白信号在确定肢体肌肉模式中的作用的基因测试。此外，我们将确定表达tcf4的细胞是否是肌肉结缔组织形成所必需的前体。这些实验将为肌肉和肌肉结缔组织的正常发育以及Wnt/ β -连环蛋白信号在调节其发育中的作用提供重要的见解。肌肉和肌肉结缔组织发育的中断可导致严重的肌肉骨骼疾病，如杜氏肌营养不良症和乌尔里希先天性肌营养不良症。我们的实验结果将为我们了解这些疾病的病因提供重要的新见解。

DESCRIPTION (provided by applicant): Development of the vertebrate musculoskeletal system requires the coordinated morphogenesis of muscle, muscle connective tissue, tendon, and skeleton. In the limb, muscle derives from migratory precursors originating from the somites, while the muscle connective tissue, tendons and skeletal elements derive from the mesoderm of the emerging lateral-plate derived limb bud. As the muscle precursors migrate into the limb, they must differentiate into myofibers, become correctly patterned into distinct anataomical muscles, and be assemebled into a functional musculoskeleton. How the over 40 limb muscles are patterned and muscle and muscle connective tissue morphogenesis coordinated is the subject of this proposal. Classical studies had suggested that lateral plate, limb mesodermal signals are important patterning muscle. However, neither the molecular nature of the signal nor the tissue producing it was known. Recently we have identified a population of lateral plate, limb mesodermal cells that expresses the transcription factor Tcf4, a downstream effector of the Wnt/beta-catenin signaling pathway, and that is critical for muscle patterning. Functional studies in the chick suggest that Tcf4-expressing cells establish a prepattern in the limb mesoderm that determines where muscle precursors differentiate and thus where individual muscles will form and the ultimate limb muscle pattern. In addition, preliminary studies indicate that Tcf4-expressing cells are the precursors of the muscle connective tissue, a tissue of fundamental importance to the form and function of the musculoskeleton and whose development has been largely unstudied because of the lack of early molecular markers. We propose to test genetically in the mouse the role of limb mseodermal Tcf4- expressing cells and Wnt/beta-catenin signaling in determining the pattern of limb muscles. In addition, we will determine whether Tcf4-expressing cells are precursors necessary for formation of muscle connective tissue. These experiments will provide important insights into the normal development of muscle and muscle connective tissue and the role of Wnt/beta-catenin signaling in regulating their development. Disruptions in the development of muscle and muscle connective tissues can result in severe musculoskeltal disorders, such as Duchenne's muscular dystrophy and Ullrich congenital muscular dystrophy. Results from our experiments will give us important new insights into the etiology of these diseases.