Wnt/β-catenin signaling regulates vertebrate limb regeneration

Abstract

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 ␤-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.Supplemental material is available at http://www.genesdev.org.

Beyond early development: Xenopus as an emerging model for the study of regenerative mechanisms

“…In the limb, regeneration was enhanced by infection of regenerating limbs with an activated ␤-catenin adenovirus (Ad-CA-␤-catenin) at a stage when regeneration success normally declines. The same treatment, though, did not rescue regeneration ability at a later stage when regeneration success is at its lowest (Kawakami et al, 2006). Very recently, a role for noncanonical Wnt signaling has also been demonstrated during tail regeneration.…”

“…Overexpression of HS-dkk-1 at the beginning of regeneration is sufficient to efficiently inhibit both tail and limb regeneration in Xenopus. This role of canonical Wnt signaling mirrors axolotl regeneration, where it has been shown that overexpression of dkk-1 in the amputated limb by adenovirus delivery abolishes regeneration (Kawakami et al, 2006). The pathway can also be overstimulated either by over-expressing activated ␤-catenin or with the compound BIO, a Gsk-3␤ inhibitor and thus an activator of Wnt/␤ signaling.…”

“…Some labs have seen nonregenerative limbs at st. 54 while others still report toe regeneration at st. 57 Kawakami et al, 2006). This can cause problems when analysing results from potential gain and loss of function experiments.…”

“…It has been used many times in Xenopus and zebrafish to dissect a specific molecular pathway used during regeneration (see Section 2.2; Beck et al, 2003Beck et al, , 2006Lee et al, 2005;Stoick-Cooper et al, 2007b;Yokoyama et al, 2007;Lin and Slack, 2008). To direct the spatial action of a protein more precisely, beads soaked in recombinant protein solution or cell aggregates expressing a specific protein have been grafted into the amputation stump Satoh et al, 2005a;Sugiura et al, 2008) and virus infection has also been used (Kawakami et al, 2006).…”

“…In the past few years, several studies demonstrated a role for the Wnt/␤-catenin signaling pathway during regeneration (Kawakami et al, 2006;Yokoyama et al, 2007;Lin and Slack, 2008;Sugiura et al, 2008). Wnt signaling can be blocked by over-expressing the secreted antagonist dickkopf-1 (Dkk-1) using a heat inducible transgene (HS-dkk-1).…”