Journal
SCIENCE
Volume 323, Issue 5917, Pages 1050-1053Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1168755
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Funding
- Swiss National Science Foundation [3100A0-100240, 3100A0-113866, 3100A0- 113617, 3100A0- 112607]
- Novartis Foundation
- NIH [2R01DE12324-12, R01DE16329]
- FCT [SFRH/BD/24301/2005]
- University of Basel
- Fundação para a Ciência e a Tecnologia [SFRH/BD/24301/2005] Funding Source: FCT
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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.
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