Alone among vertebrates, urodele amphibians are able to regenerate lost body parts as adults. Our strategy is to use axolotls (Ambvstoma mexicanum! to discover the signals that trigger the regeneration response, in the belief that these signals have enormous potential and consequences for human health. Our long term goals are to identify the regeneration enabling signals in limbs, in order to support progress towards the eventual application of these molecules to the Specific Aims. In the first, we will use assays derived from the extensive experimental history of regeneration of limbs, to test the roles of several signaling molecules known to be essential for limb development. These assays will use virally driven ectopic expression to examine the signals that initiate regeneration, those that are needed to establish a blastema, as well as those that are required for intercalary growth between the new limb tip and the amputation plane. We will test the role of fibroblast growth factors in the initiation of outgrowth, the role of bone morphogenetic proteins in promoting healing and inhibiting regeneration, the role of sonic hedgehog in providing the asymmetry needed to establish the blastema, and the role on Wnt factors in intercalary growth. In the second Specific Aim, we will generate a library of cDNAs made from regenerating limbs at different stages, and screen it with forward and reverse subtracted probes to enrich it for genes expressed differentially during regeneration. The library will be arrayed for efficient use, and screened with stage specific probes to identify genes expressed at different times in regeneration; We are especially interested in any novel factors that might be involved in transforming the differentiated limb stump into a blastema. Candidate genes will be assayed as described for known signaling molecules. The tools and knowledge are in place to attack complex systems, and understanding regeneration is likely to lead to new approaches and therapies for replacing or repairing lost, damaged or diseased parts of the body.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Javois, Lorette Claire
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University of California Irvine
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Ghosh, Sukla; Roy, Stephane; Seguin, Carl et al. (2008) Analysis of the expression and function of Wnt-5a and Wnt-5b in developing and regenerating axolotl (Ambystoma mexicanum) limbs. Dev Growth Differ 50:289-97
Satoh, Akira; Gardiner, David M; Bryant, Susan V et al. (2007) Nerve-induced ectopic limb blastemas in the Axolotl are equivalent to amputation-induced blastemas. Dev Biol 312:231-44
Gardiner, David M (2005) Ontogenetic decline of regenerative ability and the stimulation of human regeneration. Rejuvenation Res 8:141-53
Endo, Tetsuya; Bryant, Susan V; Gardiner, David M (2004) A stepwise model system for limb regeneration. Dev Biol 270:135-45
Roy, Stephane; Gardiner, David M (2002) Cyclopamine induces digit loss in regenerating axolotl limbs. J Exp Zool 293:186-90
Bryant, Susan V; Endo, Tetsuya; Gardiner, David M (2002) Vertebrate limb regeneration and the origin of limb stem cells. Int J Dev Biol 46:887-96
Gardiner, David M; Endo, Tetsuya; Bryant, Susan V (2002) The molecular basis of amphibian limb regeneration: integrating the old with the new. Semin Cell Dev Biol 13:345-52
Carlson, M R; Komine, Y; Bryant, S V et al. (2001) Expression of Hoxb13 and Hoxc10 in developing and regenerating Axolotl limbs and tails. Dev Biol 229:396-406
Roy, S; Gardiner, D M; Bryant, S V (2000) Vaccinia as a tool for functional analysis in regenerating limbs: ectopic expression of Shh. Dev Biol 218:199-205
Yang, E V; Gardiner, D M; Carlson, M R et al. (1999) Expression of Mmp-9 and related matrix metalloproteinase genes during axolotl limb regeneration. Dev Dyn 216:2-9

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