Wnt signaling restores evolutionary loss of regenerative potential inHydra

The regenerative potential of animals varies widely, even among closely-related species. In a comparative study of regeneration across theHydragenus, we found that while most species exhibit robust whole-body regeneration,Hydra oligactisand other members of the Oligactis clade consistently fail to regenerate their feet. To investigate the mechanisms underlying this deficiency, we analyzed transcriptional responses during head and foot regeneration inH. oligactis. Our analysis revealed that the general injury response inH. oligactislacks activation of Wnt signaling, a pathway essential forHydra vulgarisfoot regeneration. Notably, transient treatment with a Wnt agonist inH. oligactistriggered a foot-specific transcriptional program, successfully rescuing foot regeneration. Our transcriptional profiling also revealeddlx2as a likely high-level regulator of foot regeneration, dependent on Wnt signaling activation. Our study establishes a comparative framework for understanding the molecular basis of regeneration and its evolutionary loss in closely-related species.