Sonic hedgehog and Fgf-4 act through a signaling cascade and feedback loop to integrate growth and patterning of the developing limb bud.
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.
Laufer
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E
Department of Genetics Harvard Medical School, Boston, Massachusetts 02115.
Nelson
C E
CE
Johnson
R L
RL
Morgan
B A
BA
Tabin
C
C
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
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