Erythropoietin-Mediated Neuroprotection in Insects Suggests a Prevertebrate Evolution of Erythropoietin-Like...

The cytokine erythropoietin (Epo) mediates protective and regenerative functions in mammalian nervous systems via activation of poorly characterized receptors that differ from the "classical" homodimeric Epo receptor expressed on erythroid progenitor cells. Epo genes have been identified in vertebrate species ranging from human to fish, suggesting that Epo signaling evolved earlier than the vertebrate lineage. Studies on insects (Locusta migratoria, Chorthippus biguttulus, Tribolium castaneum) revealed Epo-mediated neuroprotection and neuroregeneration. Recombinant human Epo (rhEpo) prevents apoptosis by binding to a janus kinase-associated receptor, stimulation of STAT transcription factors, and generation of factors that prevent the activation of proapoptotic caspases. Insect neurons were also protected by a neuroprotective but nonerythropoietic Epo splice variant, suggesting similarity with mammalian neuroprotective but not with homodimeric "classical" Epo receptors. Additionally, rhEpo promotes the regeneration of neurites in primary cultured insect brain neurons and after nerve crush in an in vivo preparation. In contrast to neuroprotective and regenerative effects shared with mammalian species, no evidence for a role of Epo signaling in the regulation of neuro- or gliogenesis was found in insects. Similar structural and functional characteristics of the Epo binding receptors, partly shared transduction pathways that prevent apoptosis and the functional implication in neuroprotective and neuroregenerative processes in both mammalian and insect species, suggest that Epo-like signaling was already established in their last common ancestor. Originally functioning as a tissue-protective response to unfavorable physiological situations, cell injury, and pathogen invasion, Epo was later adapted as a humoral regulator of erythropoiesis in the vertebrate lineage.