Vertebrate skeletal muscles are composed of two major populations of cells, slow muscle cells and fast muscle cells. These cells with their specific functions and pattern of gene expression, have become a popular system for studying mechanisms that underlie determination of cell fate. Recent studies have demonstrated that slow and fast muscle is regulated by Hedgehog secreted by the notochord, and bone morphogenetic proteins (BMPs) secreted by ectoderm cells. Hedgehogs and BMPs impose their patterning activities on responsive cells via transcription factors, that in turn regulating differentiation programs in responsive cells. Many genetic studies have implicated Glis in transducing HH and BMP signals. Several members of the Gli family are expressed in somites of Xenopus, chick, mouse and zebrafish embryos. Recent genetic studies in zebrafish have shown that a mutation in Gli2 causes a defect in slow muscle formation. The investigators have recently isolated a full length Gli4 from zebrafish. Preliminary data have shown that Gli4 is strongly expressed in paraxial mesoderm and developing somites. They hypothesize that members of the Gli family of transcription factors regulate differentiation of slow and fast muscle cell lineages in zebrafish, and that the expression of individual Glis and their ability to activate or inhibit transcription of responsive genes is controlled by Hedgehogs and BMPs. The regulation of Gli activity may occur at transcriptional, translational and/or posttranslational level (proteolysis).
The specific aim of this proposal is to investigate the expression, function and regulation of Gli4 in the differentiation of muscle cells in zebrafish embryos. The long-term goal of this study is to elucidate the molecular mechanisms behind determination of muscle-specific cell fate during embryonic development.
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