A positive feedback loop coordinates growth and patterning in the vertebrate limb

Nature. 1994 Oct 13;371(6498):609-12. doi: 10.1038/371609a0.


Limb development depends on signals from the apical ectodermal ridge and underlying mesenchyme. Fibroblast growth factor (FGF) can replace the ridge and, because Fgf4 RNA is localized to the mouse posterior ridge, we proposed that FGF4 is the endogenous ridge signal. Ridge signals control limb outgrowth and maintain the zone of polarizing activity (ZPA) at the limb posterior margin, which is important in limb pattering: a ZPA graft to limb anterior mesenchyme causes cell respecification and mirror-image duplications. Sonic hedgehog (SHH) has polarizing activity, and Shh RNA co-localizes with ZPA activity, suggesting SHH is the endogenous polarizing signal. We have investigated the molecular regulation of Fgf4 and Shh expression. We report here that Fgf4 expression in the ridge can be regulated by Shh-expressing cells. Moreover, Shh expression in mesenchyme can be activated by FGF4 in combination with retinoic acid. Once induced, Shh expression can be maintained by FGF4 alone, thus establishing a positive feedback loop between ZPA and ridge.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Polarity
  • Cell Transplantation
  • Chick Embryo
  • Extremities / embryology*
  • Feedback
  • Fibroblast Growth Factor 4
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / physiology*
  • Gene Expression Regulation
  • Genes, Homeobox
  • Hedgehog Proteins
  • Humans
  • Mesoderm / metabolism
  • Mice
  • Molecular Sequence Data
  • Proteins / genetics
  • Proteins / physiology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Signal Transduction*
  • Trans-Activators*


  • FGF4 protein, human
  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • Hedgehog Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • SHH protein, human
  • Trans-Activators
  • Fibroblast Growth Factors

Associated data

  • GENBANK/U14654