Fibroblast Growth Factor Maintains Chondrogenic Potential of Limb Bud Mesenchymal Cells by Modulating DNMT3A Recruitment

• Transient Wnt signals induce stable H3K27me3 and DNA methylation of Sox9 promoter
• FGF maintains chondrogenic competence by blocking CpG methylation of Sox9 promoter
• FGF blocks Wnt-induced recruitment of DNMT3A to the Sox9 promoter
• FGF promotes phosphorylation of DNMT3A by ERK and thereby blocks DNA methylation

SummaryThe formation of cartilage is restricted to the core of the limb bud mesenchyme by ectodermal Wnts, which can irreversibly silence expression of the prochondrogenic transcription factor Sox9. In contrast, fibroblast growth factor (FGF) signals from the apical ectodermal ridge maintain the competence of chondrogenic precursors to undergo chondrogenesis once these cells go out of the range of ectodermal Wnt signals. We have found that Wnt signals induce both a repressive chromatin mark (H3K27me3) and DNA methylation over the Sox9 promoter and that Wnt-induced irreversible silencing of the Sox9 gene requires DNA methylation of this locus, which is specifically countered by FGF signals. FGF blocks the recruitment of the de novo DNA methyltransferase, DNMT3A, to the Sox9 promoter by inducing the interaction and phosphorylation of DNMT3A by ERK1/ERK2 and thereby controls whether expression of Sox9 is either irreversibly or reversibly silenced by Wnt signals in limb bud mesenchymal cells.

Graphical AbstractFigure optionsDownload as PowerPoint slide