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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.
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