Somite-independent regeneration of the axolotl primary body axis

Primary body axis development is a highly conserved process that proceeds through somitogenesis and further subdivision into dermatome, myotome, and sclerotome. Defects in somitic-clock genes such as Hes7 lead to vertebral segmentation defects in mice and fish. Here we show that in the axolotl, Hes7 is also necessary for proper embryonic vertebral segmentation but is, surprisingly, dispensable during axolotl tail regeneration. Using genetic barcoding and fate mapping we found that during regeneration, the somitic derivatives (muscle, cartilage, tendon, fibroblasts) arose from tendon-like, Lfng ⁺ multi-potent stem cells residing at the myotendonal junction that we term “asomitic stem cells”. Throughout homeostasis and regeneration these stem cells display a distinct gene regulatory state compared to developmental progenitors with comparable lineage potential. These observations contrast to axolotl limb regeneration that proceeds via fibroblast dedifferentiation and the subsequent recapitulation of a limb developmental program. Taken together our research shows that divergent strategies are deployed between limb and tail regeneration, and that regeneration of complex body parts does not necessarily involve the complete redeployment of developmental programs.