BACKGROUND/AIMS: Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T(3)) binding results in the dissociation of co-repressors and the recruitment of co-activators to the complex, which results in full transcriptional activation. METHODS: We measured cochlear function in two knock-in mouse models: TRβ(E457A/E457A), with the TRβ co-activator binding surface (AF-2) disrupted to prevent co-activator binding; and TRβ(Δ337T/Δ337T), which is unable to bind T(3). Cochlear morphology and function were analyzed in 10-week-old normal and mutated mice. Cochlear function was determined by measuring auditory brainstem responses, cochlear tuning and compound action potential (CAP) thresholds. RESULTS: All TRβ(Δ337T/Δ337T) and 85% of the TRβ(E457A/E457A) mice presented elevated CAP thresholds (P < 0.05 or less). Five percent of the TRβ(E457A/E457A) mice presented normal CAP thresholds with broadened cochlear tuning. TRβ(E457A/E457A) and TRβ(Δ337T/Δ337T) presented developmental defects that led to a decreased width (P < 0.01) and an increased thickness (P<0.01) of the tectorial membrane. In addition, TRβ(Δ337T/Δ337T) animals showed an increased tectorial membrane area (P<0.01). CONCLUSION: Both mutations were deleterious to tectorial membrane development and led to important alterations in cochlear morphology and loss of cochlear function.
BACKGROUND/AIMS: Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T(3)) binding results in the dissociation of co-repressors and the recruitment of co-activators to the complex, which results in full transcriptional activation. METHODS: We measured cochlear function in two knock-in mouse models: TRβ(E457A/E457A), with the TRβ co-activator binding surface (AF-2) disrupted to prevent co-activator binding; and TRβ(Δ337T/Δ337T), which is unable to bind T(3). Cochlear morphology and function were analyzed in 10-week-old normal and mutated mice. Cochlear function was determined by measuring auditory brainstem responses, cochlear tuning and compound action potential (CAP) thresholds. RESULTS: All TRβ(Δ337T/Δ337T) and 85% of the TRβ(E457A/E457A) mice presented elevated CAP thresholds (P < 0.05 or less). Five percent of the TRβ(E457A/E457A) mice presented normal CAP thresholds with broadened cochlear tuning. TRβ(E457A/E457A) and TRβ(Δ337T/Δ337T) presented developmental defects that led to a decreased width (P < 0.01) and an increased thickness (P<0.01) of the tectorial membrane. In addition, TRβ(Δ337T/Δ337T) animals showed an increased tectorial membrane area (P<0.01). CONCLUSION: Both mutations were deleterious to tectorial membrane development and led to important alterations in cochlear morphology and loss of cochlear function.
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