Complete activation of thyroid hormone receptor β by T 3 is essential for normal cochlear function and morphology in mice

Claus Peter Richter, Adrian Münscher, Danielle Santana MacHado, Fredric E. Wondisford, Tania M. Ortiga-Carvalho

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)997-1008
Number of pages12
JournalCellular Physiology and Biochemistry
Volume28
Issue number5
DOIs
StatePublished - 2011

All Science Journal Classification (ASJC) codes

  • Physiology

Keywords

  • Cochlea
  • Hearing
  • Thyroid hormone receptor
  • knock-in mice

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