Sphingosine 1-phosphate-mediated activation of ezrin-radixin-moesin proteins contributes to cytoskeletal remodeling and changes of membrane properties in epithelial otic vesicle progenitors.

Hearing loss is among the most prevalent sensory impairments in humans. Cochlear implantable devices re-presentthecurrenttherapiesforhearinglossbuthavevariousshortcomings.ERM(ezrin-radixin-moesin)areafamily of adaptor proteins that link plasma membrane with actin cytoskeleton, playing a crucial role in cellmorphologyandintheformationofmembraneprotrusions.Recently,bioactivesphingolipidshaveemergedasregulators of ERM proteins. Sphingosine 1-phosphate (S1P) is a pleiotropic sphingolipid which regulates fun-damental cellularfunctions suchasproliferation,survival, migrationaswell asprocesses suchasdevelopmentandinflammationmainlyvialigationtoitsspecificreceptorsS1PR(S1P1–5).ExperimentalfindingsdemonstrateakeyroleforS1Psignalingaxisinthemaintenanceofauditoryfunction.Preservationofcellularjunctionsisafundamental function bothfor S1P and ERMproteins, crucialfor themaintenance of cochlear integrity.In thepresent work, S1P was found to activate ERM in a S1P2-dependent manner in murine auditory epithelial pro-genitorsUS/VOT-E36.S1P-inducedERMactivationpotentlycontributedtoactincytoskeletalremodelingandtotheappearanceofioniccurrentsandmembranepassivepropertieschangestypicalofmoredifferentiatedcells.Moreover, PKC and Akt activation was found to mediate S1P-induced ERM phosphorylation. The obtainedfindings contribute to demonstrate the role of S1P signaling pathway in inner ear biology and to disclose po-tential innovative therapeutical approachesin thefield of hearing loss prevention and treatment