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Science 305 (5682): 396-399

Copyright © 2004 by the American Association for the Advancement of Science

The Limb Bud Shh-Fgf Feedback Loop Is Terminated by Expansion of Former ZPA Cells

Paul J. Scherz,1 Brian D. Harfe,1,2 Andrew P. McMahon,3 Clifford J. Tabin1*

Abstract: Vertebrate limb outgrowth is driven by a positive feedback loop involving Sonic Hedgehog (Shh), Gremlin, and Fgf4. By overexpressing individual components of the loop at a time after these genes are normally down-regulated in chicken embryos, we found that Shh no longer maintains Gremlin in the posterior limb. Shh-expressing cells and their descendants cannot express Gremlin. The proliferation of these descendants forms a barrier separating the Shh signal from Gremlin-expressing cells, which breaks down the Shh-Fgf4 loop and thereby affects limb size and provides a mechanism explaining regulative properties of the limb bud.

1 Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
2 Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610–0266, USA.
3 Department of Molecular and Cellular Biology, The Biolabs, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.

* To whom correspondence should be addressed. E-mail: tabin{at}genetics.med.harvard.edu

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