Role of MEF2C in muscle development and regeneration

肌营养不良是一种使人衰弱的疾病，每3500名活产男婴中就有一名受到影响。肌营养不良症的几种治疗策略旨在卫星细胞或其他肌肉相关干细胞修复受损肌纤维的能力。重要的是，最近的证据表明，在肌肉再生过程中起作用的调节途径与在骨骼肌发育过程中起作用的生肌程序有许多共同的特征。因此，这里提出的研究的长期目标是完全定义控制骨骼肌发育的转录途径， 再生和修复。在骨骼肌发育中起关键作用的一个转录因子家族是肌细胞增强因子2（MEF 2）家族。MEF 2蛋白作为与碱性螺旋-环-螺旋（bHLH）蛋白的MyoD家族成员的组合转录复合物的一部分起作用，所述MyoD家族对于发育期间的肌肉特化和分化是必需的，并且在卫星细胞增殖和分化中也起关键作用。本文的研究将明确mef 2c基因在骨骼肌中的转录调控和遗传功能。由于MEF 2转录因子在肌肉分化中起着重要作用，因此确定这些基因在肌肉发育过程中的调控和功能非常重要。更好地了解这些发育途径对于开发基于增加骨骼肌再生能力的疗法至关重要。本研究将解决以下两个具体目标：1。探讨mef 2c在骨骼肌中的功能。在小鼠中使用条件靶向方法，mef 2c基因在骨骼肌中被特异性地消融。将使用组织学、分子标记和肌肉功能分析来分析无mef 2c的骨骼肌的发育、功能和再生能力。将通过微阵列分析鉴定下游靶标。2.明确骨骼肌mef 2c转录调控因子。最近，一种小型增强剂和 鉴定了来自MEF 2C基因的启动子片段，其足以在转基因小鼠中专门指导骨骼肌表达。这里提出的研究将定义在转基因小鼠中表达所需的顺式/反式作用元件，并将确定调节mef 2c的反式作用因子。

Muscular dystrophies are debilitating diseases that affect about one out of every 3500 live male births. Several therapeutic strategies for muscular dystrophy are aimed at the capacity of satellite cells or other muscle associated stem cells to repair damaged muscle fibers. Importantly, recent evidence has shown that the regulatory pathways functioning during muscle regeneration share many common features with the myogenic program that functions during skeletal muscle development. Thus, the long term objective of the studies proposed here is to define fully the transcriptional pathways governing skeletal muscle development, regeneration, and repair. One family of transcription factors that plays a key role in skeletal muscle development is the myocyte enhancer factor 2 (MEF2) family. MEF2 proteins function as part of a combinatorial transcriptional complex with members of the MyoD family of basic helix-loop-helix (bHLH) proteins, which are essential for muscle specification and differentiation during development and also play critical roles in satellite cell proliferation and differentiation. The studies proposed here will define the transcriptional regulation and genetic function of the mef2c gene in skeletal muscle. Because MEF2 transcription factors play an essential role in muscle differentiation, it is important to define the regulation and function of these genes during muscle development. A better understanding of these developmental pathways is essential for the development of therapies based on increasing regenerative capacity in skeletal muscle. This study will address the following two specific aims: 1. To determine the function of mef2c in skeletal muscle. Using conditional targeting approaches in mice, the mef2c gene has been specifically ablated in skeletal muscle. The development, function, and regenerative capacity of skeletal muscle without mef2c will be analyzed using histology, molecular markers and analyses of muscle function. Downstream targets will be identified by microarray analyses. 2. To define the regulators of mef2c transcription in skeletal muscle. Recently, a small enhancer and promoter fragment from the mef2c gene that is sufficient to direct expression exclusively to skeletal muscle in transgenic mice was identified. The studies proposed here will define c/s-acting elements that are required for expression in transgenic mice and will identify the trans-acting factors that regulate mef2c.