Signal relay by BMP antagonism controls the SHH/FGF4 feedback loop in vertebrate limb buds.
Outgrowth and patterning of the vertebrate limb are controlled by reciprocal interactions between the posterior mesenchyme (polarizing region) and a specialized ectodermal structure, the apical ectodermal ridge (AER). Sonic hedgehog (SHH) signalling by the polarizing region modulates fibroblast growth factor (FGF)4 signalling by the posterior AER, which in turn maintains the polarizing region (SHH/FGF4 feedback loop). Here we report that the secreted bone-morphogenetic-protein (BMP) antagonist Gremlin relays the SHH signal from the polarizing region to the AER. Mesenchymal Gremlin expression is lost in limb buds of mouse embryos homozygous for the limb deformity (Id) mutation, which disrupts establishment of the SHH/FGF4 feedback loop. Grafting Gremlin-expressing cells into ld mutant limb buds rescues Fgf4 expression and restores the SHH/FGF4 feedback loop. Analysis of Shh-null mutant embryos reveals that SHH signalling is required for maintenance of Gremlin and Formin (the gene disrupted by the ld mutations). In contrast, Formin, Gremlin and Fgf4 activation are independent of SHH signalling. This study uncovers the cascade by which the SHH signal is relayed from the posterior mesenchyme to the AER and establishes that Formin-dependent activation of the BMP antagonist Gremlin is sufficient to induce Fgf4 and establish the SHH/FGF4 feedback loop.
Zúñiga
A
A
Department of Developmental Biology, Faculty of Biology, Utrecht University, The Netherlands.
Haramis
A P
AP
McMahon
A P
AP
Zeller
R
R
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D002352:Carrier Proteins; D002460:Cell Line; D002645:Chickens; D046508:Culture Techniques; D016207:Cytokines; D004475:Ectoderm / Q000502:physiology; D005246:Feedback; D005326:Fetal Proteins / Q000502:physiology; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors / Q000502:physiology*; D000080865:Formins; D053823:Hedgehog Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D018878:Limb Buds / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators; D029867:Xenopus Proteins; D014982:Xenopus laevis; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D016207:Cytokines; D005326:Fetal Proteins; D051519:Fibroblast Growth Factor 4; D005346:Fibroblast Growth Factors; D000080865:Formins; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D029867:Xenopus Proteins; D000099176:Noggin Protein; C113178:Grem1 protein, mouse; C496445:FGF4 protein, human; C496446:Fgf4 protein, mouse; C486400:GREM1 protein, Xenopus; C486399:GREM1 protein, human; C509239:SHH protein, human