Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities.
The zone of polarizing activity (ZPA) in the posterior limb bud produces Sonic Hedgehog (Shh) protein, which plays a critical role in establishing distinct fates along the anterior-posterior axis. This activity has been modeled as a concentration-dependent response to a diffusible morphogen. Using recombinase base mapping in the mouse, we determine the ultimate fate of the Shh-producing cells. Strikingly, the descendants of the Shh-producing cells encompass all cells in the two most posterior digits and also contribute to the middle digit. Our analysis suggests that, while specification of the anterior digits depends upon differential concentrations of Shh, the length of time of exposure to Shh is critical in the specification of the differences between the most posterior digits. Genetic studies of the effects of limiting accessibility of Shh within the limb support this model, in which the effect of the Shh morphogen is dictated by a temporal as well as a spatial gradient.
Harfe
Brian D
BD
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Scherz
Paul J
PJ
Nissim
Sahar
S
Tian
Hua
H
McMahon
Andrew P
AP
Tabin
Clifford J
CJ
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000502:physiology; D004058:Diffusion; D005121:Extremities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000502:physiology; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D045522:Recombinases / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D000074290:Zinc Finger Protein Gli3; D001616:beta-Galactosidase / Q000378:metabolism
D004268:DNA-Binding Proteins; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D045522:Recombinases; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; D001616:beta-Galactosidase