Dynamic changes in the response of cells to positive hedgehog signaling during mouse limb patterning

Cell. 2004 Aug 20;118(4):505-16. doi: 10.1016/j.cell.2004.07.023.


In the vertebrate limb, the posteriorly located zone of polarizing activity (ZPA) regulates digit identity through the morphogen Sonic Hedgehog (Shh). By genetically marking Shh-responding cells in mice, we have addressed whether the cumulative influence of positive Shh signaling over time and space reflects a linear gradient of Shh responsiveness and whether Shh could play additional roles in limb patterning. Our results show that all posterior limb mesenchyme cells, as well as the ectoderm, respond to Shh from the ZPA and become the bone, muscle, and skin of the posterior limb. Further, the readout of Shh activator function integrated over time and space does not display a stable and linear gradient along the A-P axis, as in a classical morphogen view. Finally, by fate mapping Shh-responding cells in Gli2 and Gli3 mutant limbs, we demonstrate that a specific level of positive Hh signaling is not required to specify digit identities.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Blotting, Southern
  • Blotting, Western
  • Body Patterning
  • Cell Lineage
  • DNA, Complementary / metabolism
  • DNA-Binding Proteins / genetics
  • Down-Regulation
  • Extremities / embryology*
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins
  • In Situ Hybridization
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Models, Genetic
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Time Factors
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3
  • beta-Galactosidase / metabolism


  • DNA, Complementary
  • DNA-Binding Proteins
  • GLI3 protein, human
  • Gli2 protein, mouse
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • Nerve Tissue Proteins
  • RNA, Messenger
  • SHH protein, human
  • Trans-Activators
  • Transcription Factors
  • Zinc Finger Protein Gli2
  • Zinc Finger Protein Gli3
  • beta-Galactosidase