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展需要肌肉，肌肉结缔组织，肌腱和骨骼的配合形态发生。在肢体中，肌肉源自源自物体的迁移前体，而肌肉结缔组织，肌腱和骨骼元素源自新出现的侧板衍生的肢体芽的中胚层。当肌肉前体迁移到肢体中时，它们必须分化为肌纤维，正确地将其构成不同的解剖肌肉，并被评估成功能性的肌肉骨骼。该提案的主题是如何形成40多个肢体肌肉和肌肉和肌肉结缔组织形态发生的主题。古典研究表明，侧板，肢体中胚层信号是重要的图案肌肉。但是，既不知道信号的分子特性或产生的组织。最近，我们确定了表达转录因子TCF4的横向板群，肢体中胚层细胞，这是Wnt/beta-catenin信号通路的下游效应子，这对于肌肉模式至关重要。雏鸡的功能研究表明，表达TCF4的细胞在肢体中胚层中建立了预生产图案，该细胞确定肌肉前体在哪里区分，从而在何处形成单个肌肉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，这是对肌肉骨骼的形式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是未经研究的。我们建议在小鼠中遗传测试肢体Mseodermal TCF4-表达细胞和Wnt/β-catenin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的细胞是否是形成肌肉结缔组织所需的前体。这些实验将为肌肉和肌肉结缔组织的正常发育以及Wnt/beta-catenin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破坏会导致严重的肌肉菌属疾病，例如Duchenne的肌营养不良症和Ullrich先天性肌肉发达症。实验的结果将使我们对这些疾病的病因的重要新见解。