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.