Muscle and Muscle Connective Tissue Development in the Vertebrate Llmb

脊椎动物 Llmb 的肌肉和肌肉结缔组织发育

基本信息

批准号：
8089982
负责人：
Gabrielle Kardon
金额：
$ 7.77万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-10 至 2012-06-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：脊椎动物肌肉骨骼系统的发育需要肌肉、肌肉结缔组织、肌腱和骨骼的协调形态发生。在肢体中，肌肉源自体节的迁移前体，而肌肉结缔组织、肌腱和骨骼成分则源自新兴的侧板衍生肢芽的中胚层。当肌肉前体迁移到肢体中时，它们必须分化成肌纤维，正确地形成不同的解剖肌肉，并组装成功能性肌肉骨骼。本提案的主题是如何形成 40 多块肢体肌肉的图案以及如何协调肌肉和肌肉结缔组织的形态发生。经典研究表明侧板、肢体中胚层信号是重要的肌肉模式。然而，人们既不知道信号的分子性质，也不知道产生信号的组织。最近，我们鉴定了一群表达转录因子 Tcf4 的侧板、肢体中胚层细胞，Tcf4 是 Wnt/β-catenin 信号通路的下游效应子，对肌肉模式至关重要。对小鸡的功能研究表明，表达 Tcf4 的细胞在肢体中胚层中建立了一种预模式，决定了肌肉前体的分化位置，从而决定了个体肌肉的形成位置以及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，肌肉结缔组织是一种对肌肉骨骼的形式和功能至关重要的组织，但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基因测试，测试肢体中胚层 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。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细胞。这些实验将为了解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中断可能导致严重的肌肉骨骼疾病，例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提供有关这些疾病病因学的重要新见解。