title: Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud.
abstract: 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.
authors.affiliation: Department of Genetics Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: E
authors.initials: E
authors.lastname: Laufer
authors.forename: C E
authors.initials: CE
authors.lastname: Nelson
authors.forename: R L
authors.initials: RL
authors.lastname: Johnson
authors.forename: B A
authors.initials: BA
authors.lastname: Morgan
authors.forename: C
authors.initials: C
authors.lastname: Tabin
mesh_terms: D000818:Animals; D001483:Base Sequence; D019485:Bone Morphogenetic Proteins; D002450:Cell Communication; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000378:metabolism; D004475:Ectoderm / Q000378:metabolism; D004627:Embryonic Induction; D005121:Extremities / Q000196:embryology*; D005246:Feedback; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins; D008648:Mesoderm / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D015534:Trans-Activators
chemical_list: D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D051519:Fibroblast Growth Factor 4; D053823:Hedgehog Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D005346:Fibroblast Growth Factors