Muscle formation during early development is critical for normal muscle function. Many diseases disrupt muscle physiology. However, the cell and molecular networks that underlie the pathology of these diseases are not known. Because each step of muscle specification and differentiation translates to the progressive refinement of functional physiology, studying muscle development can significantly inform our understanding of muscle function and physiology. The long-term goal of our lab is to elucidate the signaling networks that lead to the carefully choreographed cell behaviors that generate functional muscle using the zebrafish model. The zebrafish is an excellent model system with which to integrate the genetic, molecular, and cell biological mechanisms that underlie muscle development. Zebrafish skeletal muscle is comprised of segmentally reiterated myotomes. These myotomes contain long muscle fibers that attach to myotome boundaries. The zebrafish myotome boundary is molecularly and functionally homologous to the mammalian tendon: it is comprised mainly of collagen and transmits muscle generated force to the skeletal system. Both muscle fiber and myotome boundary formation during development are critical for normal musculoskeletal function. Preliminary data elucidate the spatial complexity of the myotome boundary as well as the morphogenetic steps that underlie muscle fiber formation. We hypothesize that an extracellular basement membrane protein, laminin, is critical for multiple steps in muscle development.
The aims of this proposal are to: 1) test the hypothesis that laminin is necessary for the initial elongation of muscle precursor cells into long muscle fibers and determine the mechanism by which laminin is required, 2) test the hypothesis that laminin is crucial for myotome boundary maintenance and determine the underlying mechanism for this requirement, and 3) test the hypothesis that laminin and Hedgehog signaling interact during boundary morphogenesis. Our use of the embryology and genetics of the zebrafish to elucidate novel aspects of muscle development may inform and benefit treatments of both muscle/tendon diseases and traumatic/overuse injuries.
