Fibroblast growth factor maintains chondrogenic potential of limb bud mesenchymal cells by modulating DNMT3A recruitment

Cell Rep. 2014 Sep 11;8(5):1419-31. doi: 10.1016/j.celrep.2014.07.038. Epub 2014 Aug 21.


The 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chick Embryo
  • Chondrogenesis*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation
  • Fibroblast Growth Factors / pharmacology*
  • HEK293 Cells
  • Humans
  • Limb Buds / cytology
  • Limb Buds / embryology
  • Limb Buds / metabolism*
  • MAP Kinase Signaling System
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Wnt Signaling Pathway


  • SOX9 Transcription Factor
  • Fibroblast Growth Factors
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A