Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development

Nat Genet. 2000 May;25(1):83-6. doi: 10.1038/75644.


Development of the vertebrate limb bud depends on reciprocal interactions between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER). Sonic hedgehog (SHH) and fibroblast growth factors (FGFs) are key signalling molecules produced in the ZPA and AER, respectively. Experiments in chicks suggested that SHH expression in the ZPA is maintained by FGF4 expression in the AER, and vice versa, providing a molecular mechanism for coordinating the activities of these two signalling centres. This SHH/FGF4 feedback loop model is supported by genetic evidence showing that Fgf4 expression is not maintained in Shh-/- mouse limbs. We report here that Shh expression is maintained and limb formation is normal when Fgf4 is inactivated in mouse limbs, thus contradicting the model. We also found that maintenance of Fgf9 and Fgf17 expression is dependent on Shh, whereas Fgf8 expression is not. We discuss a model in which no individual Fgf expressed in the AER (AER-Fgf) is solely necessary to maintain Shh expression, but, instead, the combined activities of two or more AER-Fgfs function in a positive feedback loop with Shh to control limb development.

Publication types

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

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • Ectoderm / metabolism
  • Ectoderm / physiology
  • Egg Proteins / genetics
  • Feedback / physiology
  • Fibroblast Growth Factor 4
  • Fibroblast Growth Factors / genetics*
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation, Developmental*
  • Genes, Lethal
  • Hedgehog Proteins
  • Homeodomain Proteins
  • Integrases / genetics
  • Limb Buds / embryology*
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Proteins / genetics
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Cell Surface*
  • Signal Transduction / genetics*
  • Trans-Activators*
  • Viral Proteins*
  • Zona Pellucida / physiology
  • Zona Pellucida Glycoproteins


  • DNA-Binding Proteins
  • Egg Proteins
  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • Hedgehog Proteins
  • Homeodomain Proteins
  • MSX2 protein
  • Membrane Glycoproteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Trans-Activators
  • Viral Proteins
  • Zona Pellucida Glycoproteins
  • Fibroblast Growth Factors
  • Cre recombinase
  • Integrases