The central goal of this proposal is to understand how signals from surrounding tissues activate somite myogenesis. Although it is clear that expression of either MyoD or Myf-5 is essential for the formation of skeletal muscle, it has hitherto been unclear how these genes are activated during development. The PI has begun to address what regulatory molecules mediate the induction of MyoD and Myf-5 by signals from either the axial tissues (i.e., the neural tube/notochord) or the overlying ectoderm. He has found that the muscle promoting signals from the axial tissues can be mimicked by in vitro supplied Wnt and Shh signals. Furthermore, he has found that signals from either the overlying ectoderm or in vitro supplied Wnt and Shh signals can induce somitic expression of the paired box transcription factors, Pax-3 and Pax-7, concomitant with expression of Myf-5 and prior to that of MyoD. Moreover, infection of somites in vitro with a retrovirus encoding Pax-3 (which is normally expressed in the dermomyotome) is sufficient to induce expression of MyoD, Myf-5 and myogenin in paraxial mesoderm in the absence of inducing tissues. This finding has led the PI to speculate that the muscle-promoting signals from the axial tissues, the overlying ectoderm or in vitro supplied Wnt and Shh signals may activate somitic myogenesis via a Pax-3 dependent pathway. The focus of this proposal is to elucidate how Pax-3 activates myogenic bHLH gene expression in the somite. Pax-3 is the first identified transcription factor shown to be capable of activating the expression of MyoD and Myf-5 in somitic tissue. The major goals of this grant are focused on determining how Pax-3 activates myogenic bHLH gene expression and how this activity of Pax-3 is modulated. The goals are: 1. Determine if Pax-7 and/or an alternatively spliced isoform of Pax-3 activate somitic myogenesis. 2. Determine if MyoD and Myf-5 expression are directly or indirectly activated by Pax-3. 3. Identify somitic genes whose expression is positively or negatively regulated by Pax-3. 4. Determine how the muscle promoting activity of endogenous Pax-3 is blocked in the neural tube.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Molecular Cytology Study Section (CTY)
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Harvard University
Schools of Medicine
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Lassar, Andrew B (2017) Finding MyoD and lessons learned along the way. Semin Cell Dev Biol 72:3-9
Daoud, Georges; Kempf, Hervé; Kumar, Deepak et al. (2014) BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH. Development 141:3978-87
Kamei, Caramai N; Kempf, Hervé; Yelin, Ronit et al. (2011) Promotion of avian endothelial cell differentiation by GATA transcription factors. Dev Biol 353:29-37
Kumar, Deepak; Shadrach, Jennifer L; Wagers, Amy J et al. (2009) Id3 is a direct transcriptional target of Pax7 in quiescent satellite cells. Mol Biol Cell 20:3170-7
Cairns, Dana M; Sato, Mie Elissa; Lee, Philip G et al. (2008) A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3. Dev Biol 323:152-65
Holowacz, Tamara; Zeng, Li; Lassar, Andrew B (2006) Asymmetric localization of numb in the chick somite and the influence of myogenic signals. Dev Dyn 235:633-45