The broad goal of this research is to delineate the molecular processes that pattern limb muscles using chick as a model system. The vertebrate musculoskeletal system is essential for the structure and movement of the body, and consists of muscles surrounded by connective tissue and attached via tendons to bone. Its development requires the coordinated morphogenesis of all of these tissues. The vertebrate limb has been a classic system for studying musculoskeletal morphogenesis because of its accessibility to embryological and molecular manipulations. Previous studies have focused on skeletal morphogenesis, while relatively little is known about the development of the limb muscles and their associated connective tissue. During development, interactions between the muscle connective tissue and muscle are essential for patterning muscle. Recent studies have suggested that muscle connective tissue precursors express the transcription factor Tcf4, and that Wnt/(3-catenin signaling in these cells is critical for specifying the pattern of limb muscles. The goal of this proposal is to test how Tcf4+ lateral plate cells signal to muscle precursors to establish the pattern of these muscles, and to identify molecular interactions that regulate this Tcf4 expression and activity. I will accoplish my goals using a combination of experimental embryology, chemical and retroviral manipulations, and biochemical techniques. This research has broad relevance to the study of musculoskeletal diseases. Defects in muscle development can have severe consequences, such as Duchenne's muscular dystrophy, while disruptions in muscle connective tissue development can lead to debilitating forms of congenital muscular dystrophy, such as Ullrich congenital muscular dystrophy and Bethlem myopathy. Results from these experiments will give insights into the etiology of these diseases. ? ? ?
