title: Mouse model of enlarged vestibular aqueducts defines temporal requirement of Slc26a4 expression for hearing acquisition.
abstract: Mutations in human SLC26A4 are a common cause of hearing loss associated with enlarged vestibular aqueducts (EVA). SLC26A4 encodes pendrin, an anion-base exchanger expressed in inner ear epithelial cells that secretes HCO3- into endolymph. Studies of Slc26a4-null mice indicate that pendrin is essential for inner ear development, but have not revealed whether pendrin is specifically necessary for homeostasis. Slc26a4-null mice are profoundly deaf, with severe inner ear malformations and degenerative changes that do not model the less severe human phenotype. Here, we describe studies in which we generated a binary transgenic mouse line in which Slc26a4 expression could be induced with doxycycline. The transgenes were crossed onto the Slc26a4-null background so that all functional pendrin was derived from the transgenes. Varying the temporal expression of Slc26a4 revealed that E16.5 to P2 was the critical interval in which pendrin was required for acquisition of normal hearing. Lack of pendrin during this period led to endolymphatic acidification, loss of the endocochlear potential, and failure to acquire normal hearing. Doxycycline initiation at E18.5 or discontinuation at E17.5 resulted in partial hearing loss approximating the human EVA auditory phenotype. These data collectively provide mechanistic insight into hearing loss caused by SLC26A4 mutations and establish a model for further studies of EVA-associated hearing loss.
authors.affiliation: Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, NIH, Rockville, Maryland, USA.
authors.forename: Byung Yoon
authors.initials: BY
authors.lastname: Choi
authors.forename: Hyoung-Mi
authors.initials: HM
authors.lastname: Kim
authors.forename: Taku
authors.initials: T
authors.lastname: Ito
authors.forename: Kyu-Yup
authors.initials: KY
authors.lastname: Lee
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.forename: Kelly
authors.initials: K
authors.lastname: Monahan
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Wen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wilson
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kurima
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Saunders
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.forename: Philine
authors.initials: P
authors.lastname: Wangemann
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Friedman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Griffith
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006309:Hearing / Q000235:genetics / Q000502:physiology; D006319:Hearing Loss, Sensorineural / Q000196:embryology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D011247:Pregnancy; D000076988:Sulfate Transporters; D014723:Vestibular Aqueduct / Q000196:embryology / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D027321:Anion Transport Proteins; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; C494849:Slc26a4 protein, mouse; D000076988:Sulfate Transporters; D004318:Doxycycline