title: Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking Slc26a4/pendrin expression.
abstract: Mutations of SLC26A4 cause an enlarged vestibular aqueduct, nonsyndromic deafness, and deafness as part of Pendred syndrome. SLC26A4 encodes pendrin, an anion exchanger located in the cochlea, thyroid, and kidney. The goal of the present study was to determine whether developmental delays, possibly mediated by systemic or local hypothyroidism, contribute to the failure to develop hearing in mice lacking Slc26a4 (Slc26a4(-/-)). We evaluated thyroid function by voltage and pH measurements, by array-assisted gene expression analysis, and by determination of plasma thyroxine levels. Cochlear development was evaluated for signs of hypothyroidism by microscopy, in situ hybridization, and quantitative RT-PCR. No differences in plasma thyroxine levels were found in Slc26a4(-/-) and sex-matched Slc26a4(+/-) littermates between postnatal day 5 (P5) and P90. In adult Slc26a4(-/-) mice, the transepithelial potential and the pH of thyroid follicles were reduced. No differences in the expression of genes that participate in thyroid hormone synthesis or ion transport were observed at P15, when plasma thyroxine levels peaked. Scala media of the cochlea was 10-fold enlarged, bulging into and thereby displacing fibrocytes, which express Dio2 to generate a cochlear thyroid hormone peak at P7. Cochlear development, including tunnel opening, arrival of efferent innervation at outer hair cells, endochondral and intramembraneous ossification, and developmental changes in the expression of Dio2, Dio3, and Tectb were delayed by 1-4 days. These data suggest that pendrin functions as a HCO3- transporter in the thyroid, that Slc26a4(-/-) mice are systemically euthyroid, and that delays in cochlear development, possibly due to local hypothyroidism, lead to the failure to develop hearing.
authors.affiliation: Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506, USA. wange@vet.ksu.edu
authors.forename: Philine
authors.initials: P
authors.lastname: Wangemann
authors.forename: Hyoung-Mi
authors.initials: HM
authors.lastname: Kim
authors.forename: Sara
authors.initials: S
authors.lastname: Billings
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Xiangming
authors.initials: X
authors.lastname: Li
authors.forename: Ruchira
authors.initials: R
authors.lastname: Singh
authors.forename: David S
authors.initials: DS
authors.lastname: Sharlin
authors.forename: Douglas
authors.initials: D
authors.lastname: Forrest
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Marcus
authors.forename: Peying
authors.initials: P
authors.lastname: Fong
mesh_terms: D000818:Animals; D027963:Chloride-Bicarbonate Antiporters / Q000235:genetics / Q000502:physiology*; D003051:Cochlea / Q000254:growth & development* / Q000473:pathology; D015834:Cochlear Diseases / Q000209:etiology* / Q000473:pathology; D004594:Electrophysiology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D006309:Hearing / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007037:Hypothyroidism / Q000150:complications* / Q000473:pathology; D017403:In Situ Hybridization; D007453:Iodide Peroxidase / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000076988:Sulfate Transporters; D013974:Thyroxine / Q000097:blood; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D016326:Extracellular Matrix Proteins; D007453:Iodide Peroxidase; D008565:Membrane Proteins; D000076988:Sulfate Transporters; D013974:Thyroxine; D000097564:Iodothyronine Deiodinase Type II; C494615:Slc26A4 protein, rat; C512625:beta-tectorin, mouse
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