From Hydra to Humans: Head Activator in Neurogenesis and Neurorepair

Hydra vulgaris, an ancient cnidarian, exhibits remarkable regenerative and neurogenic abilities, mediated by morphogenetic peptides, particularly the head activator peptide. This neuropeptide appears to regulate cell proliferation, differentiation, and nerve net maintenance in hydra and, surprisingly, exerts similar mitogenic and neurogenic effects in mammalian systems. Despite early enthusiasm, research on head activator has declined, due to controversies about its genetic origin, receptor identity, and artefacts generated during isolation. Nonetheless, a synthetic variant of head activator corresponding to the described sequence has consistently exhibited strong biological activity in a variety of mammalian cells. Experimental evidence implicates the sortilin-related receptor (SorLA) as a primary receptor in mammals, with potential modulatory roles for the G-protein-coupled receptor GPR37. This review consolidates current knowledge on the evolutionary context, molecular characteristics, and functional activities of head activator. Insights from mammalian systems highlight its pleiotropic effects across species. Given its neuroprotective, regenerative, and immunomodulatory properties, head activator may merit reconsideration as a therapeutic candidate for neurodegenerative disorders and regenerative medicine.