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Science 323 (5917): 1050-1053

Copyright © 2009 by the American Association for the Advancement of Science

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

Jean-Denis Bénazet,1 Mirko Bischofberger,2 Eva Tiecke,1 Alexandre Gonçalves,1 James F. Martin,3 Aimée Zuniga,1 Felix Naef,2 Rolf Zeller1*

Abstract: 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.

1 Developmental Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
2 Computational Systems Biology Group, Ecole Polytechnique Federale de Lausanne, Swiss Institute for Experimental Cancer Research and Swiss Institute of Bioinformatics, AAB 0 21 Station 15, CH-1015 Lausanne, Switzerland.
3 Texas A&M Health Science Center, Institute of Biosciences and Technology, 2121 West Holcombe Boulevard, Room 907, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: rolf.zeller{at}

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