von Willebrand factor D and EGF domains is an evolutionarily conserved and required feature of blastemas capable of multitissue appendage regeneration

Regenerative ability varies tremendously across species. A common feature of regeneration of appendages such as limbs, fins, antlers, and tails is the formation of a blastema—a transient structure that houses a pool of progenitor cells that can regenerate the missing tissue. We have identified the expression of von Willebrand factor D and EGF domains (vwde) as a common feature of blastemas capable of regenerating limbs and fins in a variety of highly regenerative species, including axolotl (Ambystoma mexicanum), lungfish (Lepidosiren paradoxa), and Polpyterus (Polypterus senegalus). Further, vwde expression is tightly linked to the ability to regenerate appendages in Xenopus laevis. Functional experiments demonstrate a requirement for vwde in regeneration and indicate that Vwde is a potent growth factor in the blastema. These data identify a key role for vwde in regenerating blastemas and underscore the power of an evolutionarily informed approach for identifying conserved genetic components of regeneration. Identification of a gene, von Willebrand Factor D and EGF Repeats (vwde), whose expression is highly enriched in axolotl limb blastemas prompted comparative experimentation in lungfish, Polypterus, and Xenopus. Vwde expression is induced in key tissues during regeneration in all four models (fins in lungfish and polypterus; tail in Xenopus embryos; limbs in axolotl). Functional experimentation in axolotl supports a role for vwde in promoting the growth of blastema as well as in patterning the regenerate limb. Research Highlights vwde expression is a common feature of blastemas capable of fin and limb regeneration. vwde expression is tightly tied to regeneration‐competency. vwde is required for axolotl limb regeneration, with transient knockdown resulting in severe endpoint phenotypes.