The limb bud Shh-Fgf feedback loop is terminated by expansion of former ZPA cells.
Vertebrate limb outgrowth is driven by a positive feedback loop involving Sonic Hedgehog (Shh), Gremlin, and Fgf4. By overexpressing individual components of the loop at a time after these genes are normally down-regulated in chicken embryos, we found that Shh no longer maintains Gremlin in the posterior limb. Shh-expressing cells and their descendants cannot express Gremlin. The proliferation of these descendants forms a barrier separating the Shh signal from Gremlin-expressing cells, which breaks down the Shh-Fgf4 loop and thereby affects limb size and provides a mechanism explaining regulative properties of the limb bud.
Scherz
Paul J
PJ
Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Harfe
Brian D
BD
McMahon
Andrew P
AP
Tabin
Clifford J
CJ
D000818:Animals; D002455:Cell Division; D002642:Chick Embryo; D016207:Cytokines; D015536:Down-Regulation; D025461:Feedback, Physiological; D051519:Fibroblast Growth Factor 4; D051524:Fibroblast Growth Factor 8; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018878:Limb Buds / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation
D016207:Cytokines; D051519:Fibroblast Growth Factor 4; D051524:Fibroblast Growth Factor 8; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; C113178:Grem1 protein, mouse; C484726:Fgf17 protein, mouse; C496446:Fgf4 protein, mouse; C496457:Fgf8 protein, mouse; C496460:Fgf9 protein, mouse; C465570:Shh protein, mouse