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Differentiation. 2010 Jan;79(1):31-40. doi: 10.1016/j.diff.2009.08.008. Epub 2009 Sep 25.

Canonical Wnt signaling regulates Foxc1/2 expression in P19 cells.

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  • 1Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.


FOXC1 and FOXC2 are forkhead/winged-helix transcription factors expressed in paraxial mesoderm and somites. Emphasizing the importance of FOXC1/2 during embryonic development, double-knockout mice lacking the alleles for both Foxc1 and Foxc2 failed to form segmented somites and undergo myogenesis. The present study aims to determine upstream factors that regulate Foxc1/2 expression during the differentiation of P19 cells into skeletal muscle. Previous work had shown that dominant-negative forms of beta-catenin, Gli2, and Meox1 could inhibit distinct stages of skeletal myogenesis in P19 cells. In the presence of a dominant-negative beta-catenin fusion protein, Foxc1/2 transcripts were not upregulated and neither were markers of somitogenesis/myogenesis, including Meox1, Pax3 and MyoD. Conversely, inhibition of GSK3 by LiCl or overexpression of activated beta-catenin in aggregated P19 cells resulted in enhancement of Foxc1/2 expression, indicating that FOX transcription may be under the control of Wnt signaling. Supporting this hypothesis, beta-catenin bound to conserved regions upstream of Foxc1 during P19 cell differentiation and drove transcription from this region in a promoter assay. In addition, ectopic expression of a dominant-negative Meox1 or Gli2 resulted in decreased Foxc1/2 transcript levels, correlating with inhibition of skeletal myogenesis. Overexpression of Gli2 was also sufficient to upregulate Foxc1/2 transcript levels and induce skeletal myogenesis. In summary, Foxc1/2 expression is dependent on a complex interplay from various signaling inputs from the Wnt and Shh pathways during early stages of in vitro skeletal myogenesis.

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