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Science 318 (5851): 772-777

Copyright © 2007 by the American Association for the Advancement of Science

Molecular Basis for the Nerve Dependence of Limb Regeneration in an Adult Vertebrate

Anoop Kumar,1* James W. Godwin,1* Phillip B. Gates,1 A. Acely Garza-Garcia,2 Jeremy P. Brockes1{dagger}

Abstract: The limb blastemal cells of an adult salamander regenerate the structures distal to the level of amputation, and the surface protein Prod 1 is a critical determinant of their proximodistal identity. The anterior gradient protein family member nAG is a secreted ligand for Prod 1 and a growth factor for cultured newt blastemal cells. nAG is sequentially expressed after amputation in the regenerating nerve and the wound epidermis—the key tissues of the stem cell niche—and its expression in both locations is abrogated by denervation. The local expression of nAG after electroporation is sufficient to rescue a denervated blastema and regenerate the distal structures. Our analysis brings together the positional identity of the blastema and the classical nerve dependence of limb regeneration.

1 Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
2 Division of Molecular Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: j.brockes{at}

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   Abstract »    Full Text »    PDF »
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J Hand Surg Eur Vol.
   Abstract »    Full Text »    PDF »
Transcriptional components of anteroposterior positional information during zebrafish fin regeneration.
G. Nachtrab, K. Kikuchi, V. A. Tornini, and K. D. Poss (2013)
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   Abstract »    Full Text »    PDF »
Pseudotyped retroviruses for infecting axolotl in vivo and in vitro.
J. L. Whited, S. L. Tsai, K. T. Beier, J. N. White, N. Piekarski, J. Hanken, C. L. Cepko, and C. J. Tabin (2013)
Development 140, 1137-1146
   Abstract »    Full Text »    PDF »
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A. Gupta, D. Wodziak, M. Tun, D. M. Bouley, and A. W. Lowe (2013)
J. Biol. Chem. 288, 4321-4333
   Abstract »    Full Text »    PDF »
Gene expression patterns specific to the regenerating limb of the Mexican axolotl.
J. R. Monaghan, A. Athippozhy, A. W. Seifert, S. Putta, A. J. Stromberg, M. Maden, D. M. Gardiner, and S. R. Voss (2012)
Biology Open 1, 937-948
   Abstract »    Full Text »    PDF »
A new zebrafish bone crush injury model.
S. Sousa, F. Valerio, and A. Jacinto (2012)
Biology Open 1, 915-921
   Abstract »    Full Text »    PDF »
Inducible genetic system for the axolotl.
J. L. Whited, J. A. Lehoczky, and C. J. Tabin (2012)
PNAS 109, 13662-13667
   Abstract »    Full Text »    PDF »
Diversity in Genetic In Vivo Methods for Protein-Protein Interaction Studies: from the Yeast Two-Hybrid System to the Mammalian Split-Luciferase System.
B. Stynen, H. Tournu, J. Tavernier, and P. Van Dijck (2012)
Microbiol. Mol. Biol. Rev. 76, 331-382
   Abstract »    Full Text »    PDF »
Beyond the cell: The cell biology of regeneration.
R. S. King and P. A. Newmark (2012)
J. Cell Biol. 196, 553-562
   Abstract »    Full Text »    PDF »
AGR2 Gene Function Requires a Unique Endoplasmic Reticulum Localization Motif.
A. Gupta, A. Dong, and A. W. Lowe (2012)
J. Biol. Chem. 287, 4773-4782
   Abstract »    Full Text »    PDF »
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A. Kumar, J.-P. Delgado, P. B. Gates, G. Neville, A. Forge, and J. P. Brockes (2011)
PNAS 108, 13588-13593
   Abstract »    Full Text »    PDF »
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A. Dong, A. Gupta, R. K. Pai, M. Tun, and A. W. Lowe (2011)
J. Biol. Chem. 286, 18301-18310
   Abstract »    Full Text »    PDF »
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R. A. Blassberg, A. Garza-Garcia, A. Janmohamed, P. B. Gates, and J. P. Brockes (2011)
J. Cell Sci. 124, 47-56
   Abstract »    Full Text »    PDF »
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A. A. Garza-Garcia, P. C. Driscoll, and J. P. Brockes (2010)
Integr. Comp. Biol. 50, 528-535
   Abstract »    Full Text »    PDF »
Branching Takes Nerve.
J. R. Rock and B. L. M. Hogan (2010)
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   Abstract »    Full Text »    PDF »
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M. Looso, T. Borchardt, M. Kruger, and T. Braun (2010)
Mol. Cell. Proteomics 9, 1157-1166
   Abstract »    Full Text »    PDF »
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V. Agrawal, S. A. Johnson, J. Reing, L. Zhang, S. Tottey, G. Wang, K. K. Hirschi, S. Braunhut, L. J. Gudas, and S. F. Badylak (2010)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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T. S. Stappenbeck and H. Miyoshi (2009)
Science 324, 1666-1669
   Abstract »    Full Text »    PDF »
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E. Tanaka and B. Galliot (2009)
Development 136, 349-353
   Abstract »    Full Text »    PDF »
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M. Kragl, D. Knapp, E. Nacu, S. Khattak, E. Schnapp, H.-H. Epperlein, and E.M. Tanaka (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Tail Regeneration in Xenopus laevis as a Model for Understanding Tissue Repair.
A.-S. Tseng and M. Levin (2008)
Journal of Dental Research 87, 806-816
   Abstract »    Full Text »    PDF »
D. L. Stocum (2007)
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