Deafness and permanently reduced potassium channel gene expression and function in hypothyroid Pit1dw mutants.
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.
Mustapha
Mirna
M
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109-5618, USA.
Fang
Qing
Q
Gong
Tzy-Wen
TW
Dolan
David F
DF
Raphael
Yehoash
Y
Camper
Sally A
SA
Duncan
R Keith
RK
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D003638:Deafness / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D018072:Hair Cells, Auditory, Outer / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D007037:Hypothyroidism / Q000150:complications* / Q000235:genetics; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission / Q000379:methods; D020409:Molecular Motor Proteins / Q000235:genetics / Q000378:metabolism; D017084:Otoacoustic Emissions, Spontaneous / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D013316:Stria Vascularis / Q000473:pathology; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism; D013680:Tectorial Membrane / Q000473:pathology / Q000648:ultrastructure; D050817:Transcription Factor Pit-1 / Q000235:genetics*; D014463:Ultrasonography; D000098854:Kcnj10 Channel
D051656:KCNQ Potassium Channels; D020409:Molecular Motor Proteins; D024661:Potassium Channels, Inwardly Rectifying; D016708:Synaptophysin; D050817:Transcription Factor Pit-1; D000098854:Kcnj10 Channel; C492167:Kcnq4 protein, mouse; C494185:Pou1f1 protein, mouse; C498720:Pres protein, mouse