title: Tmprss3, a transmembrane serine protease deficient in human DFNB8/10 deafness, is critical for cochlear hair cell survival at the onset of hearing.
abstract: Mutations in the type II transmembrane serine protease 3 (TMPRSS3) gene cause non-syndromic autosomal recessive deafness (DFNB8/10), characterized by congenital or childhood onset bilateral profound hearing loss. In order to explore the physiopathology of TMPRSS3 related deafness, we have generated an ethyl-nitrosourea-induced mutant mouse carrying a protein-truncating nonsense mutation in Tmprss3 (Y260X) and characterized the functional and histological consequences of Tmprss3 deficiency. Auditory brainstem response revealed that wild type and heterozygous mice have normal hearing thresholds up to 5 months of age, whereas Tmprss3(Y260X) homozygous mutant mice exhibit severe deafness. Histological examination showed degeneration of the organ of Corti in adult mutant mice. Cochlear hair cell degeneration starts at the onset of hearing, postnatal day 12, in the basal turn and progresses very rapidly toward the apex, reaching completion within 2 days. Given that auditory and vestibular deficits often co-exist, we evaluated the balancing abilities of Tmprss3(Y260X) mice by using rotating rod and vestibular behavioral tests. Tmprss3(Y260X) mice effectively displayed mild vestibular syndrome that correlated histologically with a slow degeneration of saccular hair cells. In situ hybridization in the developing inner ear showed that Tmprss3 mRNA is localized in sensory hair cells in the cochlea and the vestibule. Our results show that Tmprss3 acts as a permissive factor for cochlear hair cells survival and activation at the onset of hearing and is required for saccular hair cell survival. This mouse model will certainly help to decipher the molecular mechanisms underlying DFNB8/10 deafness and cochlear function.
authors: INSERM U 583, Institut des Neurosciences, Hôpital Saint Eloi, 34091 Montpellier, France.
authors: Lydie
authors: L
authors: Fasquelle
authors: Hamish S
authors: HS
authors: Scott
authors: Marc
authors: M
authors: Lenoir
authors: Jing
authors: J
authors: Wang
authors: Guy
authors: G
authors: Rebillard
authors: Sophie
authors: S
authors: Gaboyard
authors: Stéphanie
authors: S
authors: Venteo
authors: Florence
authors: F
authors: François
authors: Anne-Laure
authors: AL
authors: Mausset-Bonnefont
authors: Stylianos E
authors: SE
authors: Antonarakis
authors: Elizabeth
authors: E
authors: Neidhart
authors: Christian
authors: C
authors: Chabbert
authors: Jean-Luc
authors: JL
authors: Puel
authors: Michel
authors: M
authors: Guipponi
authors: Benjamin
authors: B
authors: Delprat
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival; D003051:Cochlea / Q000378:metabolism*; D005260:Female; D006198:Hair Cells, Auditory / Q000166:cytology; D006367:HeLa Cells; D006309:Hearing / Q000502:physiology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D057057:Serine Proteases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D057057:Serine Proteases; C559262:Tmprss3 protein, mouse