期刊
JOURNAL OF NEUROSCIENCE
卷 29, 期 4, 页码 1212-1223出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4957-08.2009
关键词
secondary hypothyroidism; tectorial membrane; KCNQ1; KCNQ4; KCNJ10; prestin; POU1F1
资金
- Deafness Research Foundation
- March of Dimes [6-FY08-262]
- National Institutes of Health [DC05053, P30 DC05188, DC05401]
- University of Michigan Office of the Vice President for Research
- Biomedical Research Council
- Clinical and Translational Science Award
The absence of thyroid hormone (TH) during late gestation and early infancy can cause irreparable deafness in both humans and rodents. A variety of rodent models have been used in an effort to identify the underlying molecular mechanism. Here, we characterize a mouse model of secondary hypothyroidism, pituitary transcription factor 1 (Pit1(dw)), which has profound, congenital deafness that is rescued by oral TH replacement. These mutants have tectorial membrane abnormalities, including a prominent Hensen's stripe, elevated beta-tectorin composition, and disrupted striated-sheet matrix. They lack distortion product otoacoustic emissions and cochlear microphonic responses, and exhibit reduced endocochlear potentials, suggesting defects in outer hair cell function and potassium recycling. Auditory system and hair cell physiology, histology, and anatomy studies reveal novel defects of hormone deficiency related to deafness: (1) permanently impaired expression of KCNJ10 in the stria vascularis of Pit1(dw) mice, which likely contributes to the reduced endocochlear potential, (2) significant outer hair cell loss in the mutants, which may result from cellular stress induced by the lower KCNQ4 expression and current levels in Pit1(dw) mutant outer hair cells, and (3) sensory and strial cell deterioration, which may have implications for thyroid hormone dysregulation in age-related hearing impairment. In summary, we suggest that these defects in outer hair cell and strial cell function are important contributors to the hearing impairment in Pit1(dw) mice.
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