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.

XIRP2, an Actin-Binding Protein Essential for Inner Ear Hair-Cell Stereocilia

“…In Xirp2 −/− mice, the F-actin meshwork of the cuticular plates might be looser or the failure of membrane-cytoskeletal adhesion may allow the extrusion of membrane from weaker spots in the apical surface. A similar phenotype was described in Tmprss3 Y260X mutant mice (Fasquelle et al, 2011) although the protrusions were reported to be kinocilia.…”

TMPRSS13 deficiency impairs stratum corneum formation and epidermal barrier acquisition

“…Human genetics and loss of function studies in mice have revealed important and surprisingly diverse roles of membrane-anchored serine proteases in mammalian development and postnatal homeostasis. These include placental morphogenesis [4, 5], neural tube closure [6], epithelial tight junction formation [7, 8], auditory and vestibular hair cell survival [9, 10], apical epithelial sodium entry [11], blood pressure [12, 13], iron homeostasis [14-16], male fertility [17, 18], and skin development.…”

N-Myc and L-Myc are essential for hair cell formation but not maintenance

“…Hair cell damage can result from developmental malformations, post-developmental insults (Dror and Avraham, 2010), or late-onset effects of mutations (Fasquelle et al, 2011) of either cochlear (hearing) or vestibular (balance) hair cells. Regardless of etiology, loss of hair cells is irreversible in mammals.…”