Skeletal muscles are comprised of two major cell types, slow and fast, that have distinct physiological, biochemical, morphological and developmental properties. The long-term goals of this work are to understand the mechanisms that regulate the formation and patterning of these different muscle types and how these mechanisms are altered in muscular diseases. Previous studies of zebrafish embryos have suggested that Hedgehog (Hh) produced by notochord and floor plate acts locally to specify slow muscle. Even though muscle precursor cells throughout the somite are apparently competent to respond to Hh, only a single monolayer precisely adjacent to the source of Hh, forms slow muscle. The proposed studies will use embryological and genetic methods to test a new hypothesis that accounts for this remarkably precise patterning: Two mechanisms limit the inductive action of Hh to immediately adjacent cells. First, notochord induces a subset of muscle precursors, in an Hh independent manner, to form adaxial cells, an epithelial monolayer that blankets the notochord. Then, in response to Hh signaling, cells in this monolayer express high levels of Patched and Hedgehog interacting protein that bind Hh at high affinity and limit its action. Thus, adaxial cells adjacent to the notochord receive high levels of Hh that induces them to become slow muscle, while at the same time, they reduce Hh signaling to more lateral cells that consequently form fast muscle.
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