Wnt signaling restores evolutionary loss of robust foot regeneration rates in Hydra

Abstract The regenerative potential of animals varies widely, even among closely related species. In a comparative study of regeneration across the Hydra genus, we found that while most species exhibit robust whole-body regeneration, Hydra oligactis and other members of the Oligactis clade display substantially reduced rates of foot regeneration. To investigate the mechanisms underlying this deficiency, we analyzed transcriptional responses during head and foot regeneration in H. oligactis . Our analysis revealed that the general injury response in H. oligactis lacks strong activation of Wnt signaling, a pathway essential for Hydra vulgaris foot regeneration. Notably, transient treatment with a Wnt agonist in H. oligactis triggered a foot-specific transcriptional program, significantly increasing rates of foot regeneration. Our transcriptional profiling also revealed dlx2 as 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 in Hydra and provides a new platform for investigating the evolution of regenerative mechanisms.