The Wnt/β-catenin pathway regulates Gli-mediatedMyf5expression during somitogenesis

Abstract

Canonical Wnt/␤-catenin signaling regulates the activation of the myogenic determination gene Myf5 at the onset of myogenesis, but the underlying molecular mechanism is unknown. Here, we report that the Wnt signal is transduced in muscle progenitor cells by at least two Frizzled (Fz) receptors (Fz1 and/or Fz6), through the canonical ␤-catenin pathway, in the epaxial domain of newly formed somites. We show that Myf5 activation is dramatically reduced by blocking the Wnt/␤-catenin pathway in somite progenitor cells, whereas expression of activated ␤-catenin is sufficient to activate Myf5 in somites but not in the presomitic mesoderm. In addition, we identified Tcf/Lef sequences immediately 5Ј to the Myf5 early epaxial enhancer. These sites determine the correct spatiotemporal expression of Myf5 in the epaxial domain of the somite, mediating the synergistic action of the Wnt/␤-catenin and the Shh/Gli pathways. Taken together, these results demonstrate that Myf5 is a direct target of Wnt/␤-catenin, and that its full activation requires a cooperative interaction between the canonical Wnt and the Shh/Gli pathways in muscle progenitor cells.

A WNT/β-Catenin Signaling Activator, R-spondin, Plays Positive Regulatory Roles during Skeletal Myogenesis

“…However, mice lacking both genes display severe defects in myogenic commitment (34), resulting in a massive loss of skeletal muscle during embryogenesis, indicating that Myf5 and MyoD have a redundant role in myogenic commitment. Embryonic Myf5 expression within the epaxial domain of the somites is regulated by the WNT1 and WNT3A ligands derived from the dorsal region of developing neural tube in mice and chicken (1,3,4). An efficient activation of Myf5 gene by WNT in the somites is synergized by SHH signaling (1,4).…”

“…Embryonic Myf5 expression within the epaxial domain of the somites is regulated by the WNT1 and WNT3A ligands derived from the dorsal region of developing neural tube in mice and chicken (1,3,4). An efficient activation of Myf5 gene by WNT in the somites is synergized by SHH signaling (1,4). Several TCF binding sites as well as SHH signaling target, a GLI transcription factor binding site, were identified within the epaxial specific enhancer region of the mouse Myf5 gene (1).…”

“…An efficient activation of Myf5 gene by WNT in the somites is synergized by SHH signaling (1,4). Several TCF binding sites as well as SHH signaling target, a GLI transcription factor binding site, were identified within the epaxial specific enhancer region of the mouse Myf5 gene (1). Mutagenesis analysis of these sites in transgenic mice showed that two TCF and GLI sites are required for robust Myf5 expression (1).…”

“…The importance of WNT signaling in skeletal myogenesis was initially demonstrated in embryonic skeletal myogenesis (1)(2)(3)(4). The WNT1 and WNT3A ligands derived from the dorsal neural tube and the surface ectoderm positively regulate skeletal myogenesis within somites via the canonical WNT/␤-catenin signaling pathway (3,4).…”

The A17 enhancer directs expression of Myf5 to muscle satellite cells but Mrf4 to myonuclei

“…This transgenic analysis has delimited regions able to direct expression at specific locations during development. In some cases, the factors that control Myf5 expression at these sites have been identified, such as sonic hedgehog/Gli and Wnt/TCF for the epaxial somite (Gustafsson et al, 2002;McDermott et al, 2005;Borello et al, 2006) or Pax3 and Six1/4 in the developing limb Giordani et al, 2007).…”