Self-Regulatory System of Interlinked Signaling Feedback Loops Controls Mouse Limb Patterning

Embryogenesis depends on self-regulatory interactions between spatially separated signaling centers, but few of these are well understood. Limb development is regulated by epithelial-mesenchymal (e-m) feedback loops between sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling involving...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2009-02, Vol.323 (5917), p.1050-1053
Main Authors: Bénazet, Jean-Denis, Bischofberger, Mirko, Tiecke, Eva, Gonçalves, Alexandre, Martin, James F, Zuniga, Aimée, Naef, Felix, Zeller, Rolf
Format: Article
Language:English
Subjects:
Alleles
Animals
Biological and medical sciences
Body Patterning
Bone Morphogenetic Protein 4 - genetics
Bone Morphogenetic Protein 4 - metabolism
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Control loops
Developmental biology
Embryos
Epithelium - embryology
Epithelium - metabolism
Feedback
Feedback, Physiological
Fibroblast Growth Factors - genetics
Fibroblast Growth Factors - metabolism
Forelimb - embryology
Forelimbs
Fundamental and applied biological sciences. Psychology
Gene dosage
Genetics
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Limb buds
Limb Buds - embryology
Limb Buds - metabolism
Medical genetics
Mesoderm - metabolism
Mice
Models, Biological
Molecular and cellular biology
Rodents
Signal Transduction
Toes - embryology
Ulna
Up regulation
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Summary:Embryogenesis depends on self-regulatory interactions between spatially separated signaling centers, but few of these are well understood. Limb development is regulated by epithelial-mesenchymal (e-m) feedback loops between sonic hedgehog (SHH) and fibroblast growth factor (FGF) signaling involving the bone morphogenetic protein (BMP) antagonist Gremlin1 (GREM1). By combining mouse molecular genetics with mathematical modeling, we showed that BMP4 first initiates and SHH then propagates e-m feedback signaling through differential transcriptional regulation of Grem1 to control digit specification. This switch occurs by linking a fast BMP4/GREM1 module to the slower SHH/GREM1/FGF e-m feedback loop. This self-regulatory signaling network results in robust regulation of distal limb development that is able to compensate for variations by interconnectivity among the three signaling pathways.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1168755