Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors.
The deafness caused by early onset hypothyroidism indicates that thyroid hormone is essential for the development of hearing. We investigated the underlying roles of the TRalpha1 and TRbeta thyroid hormone receptors in the auditory system using receptor-deficient mice. TRalpha1 and TRbeta, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TRbeta is required for hearing because TRbeta-deficient (Thrb(tm1/tm1)) mice have a defective auditory-evoked brainstem response and retarded expression of a potassium current (I(K,f)) in the cochlear inner hair cells. Here, we show that although TRalpha1 is individually dispensable, TRalpha1 and TRbeta synergistically control an extended array of functions in postnatal cochlear development. Compared with Thrb(tm1/tm1) mice, the deletion of all TRs in Thra(tm1/tm1)Thrb(tm1/tm1) mice produces exacerbated and novel phenotypes, including delayed differentiation of the sensory epithelium, malformation of the tectorial membrane, impairment of electromechanical transduction in outer hair cells, and a low endocochlear potential. The induction of I(K,f) in inner hair cells was not markedly more retarded than in Thrb(tm1/tm1) mice, suggesting that this feature of hair cell maturation is primarily TRbeta-dependent. These results indicate that distinct pathways mediated by TRbeta alone or by TRbeta and TRalpha1 together facilitate control over an extended range of functions during the maturation of the cochlea.
Rusch
A
A
Physiologisches Institut and Sektion Sensorische Biophysik, Hals-Nasen-Ohren Klinik, Röntgenweg 11, Universität Tübingen, D-72076 Tübingen, Germany.
Ng
L
L
Goodyear
R
R
Oliver
D
D
Lisoukov
I
I
Vennstrom
B
B
Richardson
G
G
Kelley
M W
MW
Forrest
D
D
D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D003051:Cochlea / Q000002:abnormalities* / Q000254:growth & development / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D025802:Electric Capacitance; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics; D006198:Hair Cells, Auditory / Q000473:pathology / Q000503:physiopathology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009024:Morphogenesis / Q000235:genetics; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000172:deficiency* / Q000235:genetics; D013680:Tectorial Membrane / Q000002:abnormalities / Q000473:pathology / Q000648:ultrastructure
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone