Developmental delays consistent with cochlear hypothyroidism contribute to failure to develop hearing in mice lacking...

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Otolaryngology

Background:

• Mutations in the SLC26A4 gene are linked to enlarged vestibular aqueduct and hearing loss, including in Pendred syndrome.
• SLC26A4 encodes pendrin, an anion exchanger vital for thyroid, kidney, and cochlear function.
• The role of developmental delays, potentially from hypothyroidism, in Slc26a4(-/-) mouse hearing loss is not fully understood.

Purpose of the Study:

• To investigate if developmental delays, possibly due to systemic or local hypothyroidism, contribute to hearing failure in Slc26a4(-/-) mice.
• To assess thyroid function and cochlear development in mice lacking Slc26a4.

Main Methods:

• Evaluated thyroid function via voltage/pH measurements, gene expression analysis, and plasma thyroxine levels.
• Assessed cochlear development using microscopy, in situ hybridization, and quantitative RT-PCR.
• Compared Slc26a4(-/-) mice with sex-matched Slc26a4(+/-) littermates.

Main Results:

• Slc26a4(-/-) mice exhibited normal plasma thyroxine levels, indicating systemic euthyroidism.
• Adult Slc26a4(-/-) mice showed reduced thyroid follicle transepithelial potential and pH.
• Cochlear development, including scala media enlargement and gene expression changes (Dio2, Dio3, Tectb), was delayed by 1-4 days in Slc26a4(-/-) mice, suggesting local hypothyroidism.

Conclusions:

• Pendrin likely functions as a bicarbonate transporter in the thyroid gland.
• Slc26a4(-/-) mice are systemically euthyroid, but exhibit delays in cochlear development.
• These cochlear developmental delays, potentially caused by local hypothyroidism, are implicated in the failure to develop hearing.