Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud

Cell. 1994 Dec 16;79(6):993-1003. doi: 10.1016/0092-8674(94)90030-2.


Proper limb growth and patterning requires signals from the zone of polarizing activity in the posterior mesoderm and from the overlying apical ectodermal ridge (AER). Sonic hedgehog and Fgf-4, respectively, have recently been identified as candidates for these signals. We have dissected the roles of these secreted proteins in early limb development by ectopically regulating their activities in a number of surgical contexts. Our results indicate that Sonic hedgehog initiates expression of secondary signaling molecules, including Bmp-2 in the mesoderm and Fgf-4 in the ectoderm. The mesoderm requires ectodermally derived competence factors, which include Fgf-4, to activate target gene expression in response to Sonic hedgehog. The expression of Sonic hedgehog and Fgf-4 is coordinately regulated by a positive feedback loop operating between the posterior mesoderm and the overlying AER. Taken together, these data provide a basis for understanding the integration of growth and patterning in the developing limb.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • Bone Morphogenetic Proteins
  • Cell Communication*
  • Chick Embryo
  • DNA-Binding Proteins / metabolism
  • Ectoderm / metabolism
  • Embryonic Induction*
  • Extremities / embryology*
  • Feedback
  • Fibroblast Growth Factor 4
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Hedgehog Proteins
  • Mesoderm / metabolism
  • Models, Biological
  • Molecular Sequence Data
  • Proteins / genetics
  • Proteins / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction*
  • Tissue Distribution
  • Trans-Activators*


  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • Fibroblast Growth Factor 4
  • Hedgehog Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Fibroblast Growth Factors