The Wnt/beta-catenin pathway regulates Gli-mediated Myf5 expression during somitogenesis.
Canonical Wnt/beta-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 beta-catenin pathway, in the epaxial domain of newly formed somites. We show that Myf5 activation is dramatically reduced by blocking the Wnt/beta-catenin pathway in somite progenitor cells, whereas expression of activated beta-catenin is sufficient to activate Myf5 in somites but not in the presomitic mesoderm. In addition, we identified Tcf/Lef sequences immediately 5' 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/beta-catenin and the Shh/Gli pathways. Taken together, these results demonstrate that Myf5 is a direct target of Wnt/beta-catenin, and that its full activation requires a cooperative interaction between the canonical Wnt and the Shh/Gli pathways in muscle progenitor cells.
Borello
Ugo
U
Stem Cell Research Institute, Dibit, H. San Raffaele, Via Olgettina 58, 20132 Milan, Italy. ugo.borello@ucsf.edu
Berarducci
Barbara
B
Murphy
Paula
P
Bajard
Lola
L
Buffa
Viviana
V
Piccolo
Stefano
S
Buckingham
Margaret
M
Cossu
Giulio
G
D000818:Animals; D024202:Electrophoretic Mobility Shift Assay; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D004627:Embryonic Induction / Q000235:genetics / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005914:Globins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019170:Somites / Q000166:cytology / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D051787:Myogenic Regulatory Factor 5; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; D005914:Globins