The proper development of the musculoskeleton requires the coordinated morphogenesis of muscle, muscle connective tissue, tendon, and skeleton. Our initial research has focused on the development of the vertebrate limb musculoskeleton. With its accessibility to embryological and molecular manipulations, the vertebrate limb has been a classic system for studying morphogenesis. During development, the limb muscle derives from migratory precursors originating from the somites, while the muscle connective tissue, tendons, and skeleton develop from the lateral plate mesodermal cells of the emerging limb bud. As the muscle precursors migrate into the limb they must differentiate into myofibers, become correctly patterned into distinct anatomical muscles, and be assembled with muscle connective tissue, tendons, and skeletal elements into a functional musculoskeletal system. Our recent research has demonstrated that limb embryonic and fetal muscle cells develop from distinct, but related progenitors and have different cell-autonomous requirements for b-catenin. In addition we have found that both muscle cell fate and patterning is determined by local extrinsic signals within the developing limb. We have determined that connective tissue fibroblasts, which express the transcription factor Tcf4 (a downstream effector of canonical Wnt/b-catenin signaling), are critical for proper muscle development. We are currently examining the role of Tcf4+ fibroblasts in regulating muscle cell fate and patterning and production of muscle connective tissue.
Vertebrate muscle has a remarkable capacity for regeneration. During the regenerative process, muscle and its surrounding connective tissue need to be repaired and structurally and functionally integrated with tendons and bones to restore musculoskeletal function. The regeneration of myofibers appears to be largely mediated by resident myogenic stem cells called satellite cells. During regeneration, satellite cells become activated, proliferate, and differentiate to repair damaged myofibers. Another important component of muscle regeneration is the transient increase of the surrounding muscle connective tissue, termed fibrosis. This fibrosis maintains the structure of the damaged muscle, but must be carefully regulated since excessive fibrosis can inhibit muscle regeneration. Our previous research has demonstrated that the great majority of satellite cells derive in development from the somites. We are currently testing the role of satellite cells and connective tissue fibroblasts in restoration of muscle and connective tissue structure and function during regeneration.
Duchenne Muscular Dystrophy (DMD) is a fatal disease affecting 1 in 3300 boys. It results from mutations in the dystrophin gene, whose protein is essential for muscle structure and function. DMD is characterized by both pathological muscle degeneration and regeneration and extensive fibrosis. Therefore interactions between connective tissue fibroblasts, satellite cells, and fibrosis are likely critical for DMD pathology. We are investigating how interactions between muscle and connective tissue contribute to the pathology of DMD.