Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2.
Hearing requires the transduction of vibrational forces by specialized epithelial cells in the cochlea known as hair cells. The human ear contains a finite number of terminally differentiated hair cells that, once lost by noise-induced damage or toxic insult, can never be regenerated. We report here that sphingosine 1-phosphate (S1P) signaling, mainly via activation of its cognate receptor S1P2, is required for the maintenance of vestibular and cochlear hair cells in vivo. Two S1P receptors, S1P2 and S1P3, were found to be expressed in the cochlea by reverse transcription-PCR and in situ hybridization. Mice that are null for both these receptors uniformly display progressive cochlear and vestibular defects with hair cell loss, resulting in complete deafness by 4 weeks of age and, with complete penetrance, balance defects of increasing severity. This study reveals the previously unknown role of S1P signaling in the maintenance of cochlear and vestibular integrity and suggests a means for therapeutic intervention in degenerative hearing loss.
Herr
Deron R
DR
Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, La Jolla, California 92037, USA.
Grillet
Nicolas
N
Schwander
Martin
M
Rivera
Richard
R
Müller
Ulrich
U
Chun
Jerold
J
D000161:Acoustic Stimulation; D000375:Aging / Q000473:pathology; D000818:Animals; D002470:Cell Survival; D003051:Cochlea / Q000254:growth & development / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003638:Deafness / Q000235:genetics / Q000473:pathology; D005106:Exploratory Behavior; D006198:Hair Cells, Auditory / Q000166:cytology* / Q000502:physiology; D018069:Hair Cells, Vestibular / Q000166:cytology / Q000502:physiology; D006309:Hearing / Q000502:physiology; D017403:In Situ Hybridization; D008246:Lysophospholipids; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009925:Organ of Corti / Q000378:metabolism / Q000473:pathology; D004856:Postural Balance / Q000502:physiology; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013216:Reflex, Startle; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012678:Sensation Disorders / Q000235:genetics / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives; D000081025:Sphingosine-1-Phosphate Receptors; D013136:Spiral Ganglion / Q000378:metabolism / Q000473:pathology; D014722:Vestibule, Labyrinth / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C501285:S1pr3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D013110:Sphingosine