FIGURE 6.

Limb regenerative ability may have evolved uniquely in caudates. Comparison of developmental mechanisms among tetrapods has revealed that urodeles possess a derived mode of limb development compared to anurans and amniotes including, absence of a morphological and molecular AER, mesenchymal restriction of canonical AER-Fgfs, absence of a positive feedback loop between Fgf and Shh signaling, and reliance on Shh-signaling to regulate proximal-distal outgrowth via cell proliferation and survival (orange line). Correlating with this unique mode of limb development, urodeles are the only extant tetrapods capable of complete limb regeneration at any post-embryonic life stage (larva, juvenile, or adult). One possible explanation for this tight correlation is that limb regenerative ability evolved within caudates as their mode of limb development was modified from the ancestral tetrapod state to reside within the mesenchymal tissue compartment (red asterisk). This opposes the hypothesis that limb and fin regenerative ability have a common origin among Sarcopterygii-with anurans and amniotes having lost limb regenerative ability (Nogueira et al., 2016). This hypothesis is based on common gene expression data derived from regeneration of cartilaginous elements in lungfish fins, a process similar to the regeneration of a cartilage spike in amputated Xenopus limbs.