Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 16 July 2004:
Vol. 305. no. 5682, pp. 396 - 399
DOI: 10.1126/science.1096966
Prev | Table of Contents | Next

Reports

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*

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb.
N. C. Butterfield, V. Metzis, E. McGlinn, S. J. Bruce, B. J. Wainwright, and C. Wicking (2009)
Development 136, 3515-3524
   Abstract »    Full Text »    PDF »
Vertebrate Limb Development: Moving from Classical Morphogen Gradients to an Integrated 4-Dimensional Patterning System.
J.-D. Benazet and R. Zeller (2009)
Cold Spring Harb Perspect Biol 1, a001339
   Abstract »    Full Text »    PDF »
Loss of connexin43-mediated gap junctional coupling in the mesenchyme of limb buds leads to altered expression of morphogens in mice.
R. Dobrowolski, G. Hertig, H. Lechner, P. Worsdorfer, V. Wulf, N. Dicke, D. Eckert, R. Bauer, H. Schorle, and K. Willecke (2009)
Hum. Mol. Genet. 18, 2899-2911
   Abstract »    Full Text »    PDF »
Limb Development Takes a Measured Step Toward Systems Analysis.
S. Mackem and M. Lewandoski (2009)
Science Signaling 2, pe33
   Abstract »    Full Text »    PDF »
A Self-Regulatory System of Interlinked Signaling Feedback Loops Controls Mouse Limb Patterning.
J.-D. Benazet, M. Bischofberger, E. Tiecke, A. Goncalves, J. F. Martin, A. Zuniga, F. Naef, and R. Zeller (2009)
Science 323, 1050-1053
   Abstract »    Full Text »    PDF »
Sall genes regulate region-specific morphogenesis in the mouse limb by modulating Hox activities.
Y. Kawakami, Y. Uchiyama, C. Rodriguez Esteban, T. Inenaga, N. Koyano-Nakagawa, H. Kawakami, M. Marti, M. Kmita, P. Monaghan-Nichols, R. Nishinakamura, et al. (2009)
Development 136, 585-594
   Abstract »    Full Text »    PDF »
Growing models of vertebrate limb development.
M. Towers and C. Tickle (2009)
Development 136, 179-190
   Abstract »    Full Text »    PDF »
A second wave of Sonic hedgehog expression during the development of the bat limb.
D. Hockman, C. J. Cretekos, M. K. Mason, R. R. Behringer, D. S. Jacobs, and N. Illing (2008)
PNAS 105, 16982-16987
   Abstract »    Full Text »    PDF »
A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb.
S. A. Vokes, H. Ji, W. H. Wong, and A. P. McMahon (2008)
Genes & Dev. 22, 2651-2663
   Abstract »    Full Text »    PDF »
Laminin-511 is an epithelial message promoting dermal papilla development and function during early hair morphogenesis.
J. Gao, M. C. DeRouen, C.-H. Chen, M. Nguyen, N. T. Nguyen, H. Ido, K. Harada, K. Sekiguchi, B. A. Morgan, J. H. Miner, et al. (2008)
Genes & Dev. 22, 2111-2124
   Abstract »    Full Text »    PDF »
Uncoupling the Role of Sonic Hedgehog in Limb Development: Growth and Specification.
P. Francis-West and R. Hill (2008)
Science Signaling 1, pe34
   Abstract »    Full Text »    PDF »
Cell tracing reveals a dorsoventral lineage restriction plane in the mouse limb bud mesenchyme.
C. G. Arques, R. Doohan, J. Sharpe, and M. Torres (2007)
Development 134, 3713-3722
   Abstract »    Full Text »    PDF »
Differential regulation of gene expression in the digit forming area of the mouse limb bud by SHH and gremlin 1/FGF-mediated epithelial-mesenchymal signalling.
L. Panman, A. Galli, N. Lagarde, O. Michos, G. Soete, A. Zuniga, and R. Zeller (2006)
Development 133, 3419-3428
   Abstract »    Full Text »    PDF »
Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression.
T. D. Capellini, G. Di Giacomo, V. Salsi, A. Brendolan, E. Ferretti, D. Srivastava, V. Zappavigna, and L. Selleri (2006)
Development 133, 2263-2273
   Abstract »    Full Text »    PDF »
Multiple roles of mesenchymal {beta}-catenin during murine limb patterning.
T. P. Hill, M. M. Taketo, W. Birchmeier, and C. Hartmann (2006)
Development 133, 1219-1229
   Abstract »    Full Text »    PDF »
Sonic Hedgehog Pathway Inhibition Alters Epididymal Function as Assessed by the Development of Sperm Motility.
T. T. Turner, H. J. Bang, S. A. Attipoe, D. S. Johnston, and J. L. Tomsig (2006)
J Androl 27, 225-232
   Abstract »    Full Text »    PDF »
Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function.
P. Lu, G. Minowada, and G. R. Martin (2006)
Development 133, 33-42
   Abstract »    Full Text »    PDF »
Reciprocal epithelial-mesenchymal FGF signaling is required for cecal development.
X. Zhang, T. S. Stappenbeck, A. C. White, K. J. Lavine, J. I. Gordon, and D. M. Ornitz (2006)
Development 133, 173-180
   Abstract »    Full Text »    PDF »
It Takes Time to Make a Pinky: Unexpected Insights into How SHH Patterns Vertebrate Digits.
R. Zeller (2004)
Sci. STKE 2004, pe53
   Abstract »    Full Text »    PDF »
Shh is out on a limb.
N. LeBrasseur (2004)
J. Cell Biol. 166, 608-609
   Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)