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Kawakami Y
,
Rodriguez Esteban C
,
Raya M
,
Kawakami H
,
Martí M
,
Dubova I
,
Izpisúa Belmonte JC
.
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The cellular and molecular bases allowing tissue regeneration are not well understood. By performing gain- and loss-of-function experiments of specific members of the Wnt pathway during appendage regeneration, we demonstrate that this pathway is not only necessary for regeneration to occur, but it is also able to promote regeneration in axolotl, Xenopus, and zebrafish. Furthermore, we show that changes in the spatiotemporal distribution of beta-catenin in the developing chick embryo elicit apical ectodermal ridge and limb regeneration in an organism previously thought not to regenerate. Our studies may provide valuable insights toward a better understanding of adult tissue regeneration.
Figure 1. Wnt/Beta-catenin signaling is required for limb regeneration in axolotls and Xenopus. (A) Gross morphology and scanning electron microscope (SEM) images of adult (A,B) and larvae (C,D) axolotls. (A) A fully regenerated wild-type adult axolotl forelimb develops 2 mo after amputation at the elbow level. (B) Microinjection of Ad-Axin1 after forelimb amputation prevented regeneration of the distal elements (red arrowhead). (C) SEM image of an axolotl larvae limb at the stage at which amputation was performed (stage 45). (D) Ventral view of axolotl larvae limbs 1 mo after amputation and virus injection. The right amputated limb regenerated normally (reader left side, white arrowhead), while the left amputated limb, injected with Ad-Dkk1, did not regenerate (reader right side, red arrowhead). (E) Gross morphology and SEM images of Xenopus larvae hindlimbs. (E) SEM image of the Xenopus larvae hindlimb at the amputated stage 51. (F) Ventral view of the control limb 21 d after amputation. The limb regenerated (white arrowhead) and formed the autopod. (G) Ventral view of the limb 21 d after amputation and injection of Ad-Dkk1. Dkk1 inhibited regeneration (red arrowhead), and prevented the formation of the more distallimb elements. (H) SEM image of Xenopus larvae hindlimb at the amputated stage (NF stage 54). (I) Ventral view of the limb 21 d after amputation. The limb did not regenerate when amputated at stage 54 (red arrow- head). Lateral (J) and ventral (K) views of the limb 21 d after ampu- tation and injection of Ad-CA-Beta-catenin. Beta-Catenin was able to regenerate the distallimb elements (white arrowhead, J), or partially restore regeneration of distal structures (red arrowhead, K). (L) Ventral view of a limb 21 d after amputation at the knee level at stage 58, showing lack of regeneration. (M) Ventral view of a limb 21 d after amputation and injection of Ad-CA-Beta-catenin at the knee level at NF stage 58, showing lack of regeneration. A small outgrowth is observed. In larvae shown in F, amputation with or without virus injection was done to the leftlimb while the rightlimb was left to develop normally. Orange arrows indicate the amputation level, and white and red arrowheads indicate regenerated and regeneration- defective limbs, respectively.
Supplementary Figure S1. Use of adenoviruses for gene transfer in axolotl, Xenopus, and zebrafish
Dark field (A, C, E) and bright field (B, D, F) images of the Xenopus larvae hindlimb (A, B), axolotl larvae forelimb (C, D) and adult zebrafish pectoral fin (E, F). Fluorescent image of a Xenopus hindlimb bud 3 days after amputation and injection of Ad-eGFP at stage 52 (A). Fluorescent image of an axolotl larvae forelimb 1 day after amputation and injection of Ad-eGFP (C). Fluorescent image of an adult zebrafish pectoral fin 1 day after amputation and injection of Ad-eGFP (E). Arrows indicate fluorescent signal by Ad-eGFP.
Ahn,
BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb.
2001, Pubmed
Ahn,
BMPR-IA signaling is required for the formation of the apical ectodermal ridge and dorsal-ventral patterning of the limb.
2001,
Pubmed
Akimenko,
Old questions, new tools, and some answers to the mystery of fin regeneration.
2003,
Pubmed
Bakkers,
Zebrafish DeltaNp63 is a direct target of Bmp signaling and encodes a transcriptional repressor blocking neural specification in the ventral ectoderm.
2002,
Pubmed
Bode,
Head regeneration in Hydra.
2003,
Pubmed
Brockes,
Plasticity and reprogramming of differentiated cells in amphibian regeneration.
2002,
Pubmed
Brockes,
Appendage regeneration in adult vertebrates and implications for regenerative medicine.
2005,
Pubmed
Bryant,
Vertebrate limb regeneration and the origin of limb stem cells.
2002,
Pubmed
Capdevila,
Patterning mechanisms controlling vertebrate limb development.
2001,
Pubmed
Caubit,
Possible roles for Wnt genes in growth and axial patterning during regeneration of the tail in urodele amphibians.
1997,
Pubmed
DENT,
Limb regeneration in larvae and metamorphosing individuals of the South African clawed toad.
1962,
Pubmed
Funayama,
Embryonic axis induction by the armadillo repeat domain of beta-catenin: evidence for intracellular signaling.
1995,
Pubmed
,
Xenbase
Glinka,
Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction.
1998,
Pubmed
,
Xenbase
Kawakami,
WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo.
2001,
Pubmed
Maden,
Retinoic acid, a regeneration-inducing molecule.
2003,
Pubmed
Maves,
Transdetermination in Drosophila imaginal discs: a model for understanding pluripotency and selector gene maintenance.
2003,
Pubmed
Mills,
p63 is a p53 homologue required for limb and epidermal morphogenesis.
1999,
Pubmed
Miyake,
Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome.
1996,
Pubmed
Mullins,
Large-scale mutagenesis in the zebrafish: in search of genes controlling development in a vertebrate.
1994,
Pubmed
Muneoka,
Intrinsic control of regenerative loss in Xenopus laevis limbs.
1986,
Pubmed
,
Xenbase
Niswander,
FGF-4 replaces the apical ectodermal ridge and directs outgrowth and patterning of the limb.
1993,
Pubmed
Pizette,
BMP controls proximodistal outgrowth, via induction of the apical ectodermal ridge, and dorsoventral patterning in the vertebrate limb.
2001,
Pubmed
Poss,
Induction of lef1 during zebrafish fin regeneration.
2000,
Pubmed
Poss,
Tales of regeneration in zebrafish.
2003,
Pubmed
Poss,
Roles for Fgf signaling during zebrafish fin regeneration.
2000,
Pubmed
Raya,
Activation of Notch signaling pathway precedes heart regeneration in zebrafish.
2003,
Pubmed
Slack,
Cellular and molecular mechanisms of regeneration in Xenopus.
2004,
Pubmed
,
Xenbase
Solnica-Krezel,
Efficient recovery of ENU-induced mutations from the zebrafish germline.
1994,
Pubmed
Suzuki,
Nerve-dependent and -independent events in blastema formation during Xenopus froglet limb regeneration.
2005,
Pubmed
,
Xenbase
Tanaka,
Cell differentiation and cell fate during urodele tail and limb regeneration.
2003,
Pubmed
Tickle,
Molecular basis of vertebrate limb patterning.
2002,
Pubmed
Tsonis,
Regeneration in vertebrates.
2000,
Pubmed
Whitehead,
fgf20 is essential for initiating zebrafish fin regeneration.
2005,
Pubmed
Yang,
p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.
1999,
Pubmed
