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 journalArticle

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 (PΔ337T/Δ337T animals showed an increased tectorial membrane area (P

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

Fingerprint

Thyroid Hormone Receptors
Cochlea
Cytoplasmic and Nuclear Receptors
Thyroid Hormones
Action Potentials
Co-Repressor Proteins
Tectorial Membrane
Furylfuramide
Brain Stem Auditory Evoked Potentials
Triiodothyronine
Transcriptional Activation
Ligands

Keywords

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

ASJC Scopus subject areas

  • Physiology

Cite this

Complete activation of thyroid hormone receptor β by T 3 is essential for normal cochlear function and morphology in mice. / Richter, Claus Peter; Münscher, Adrian; Santana MacHado, Danielle; Wondisford, Fredric E.; Ortiga-Carvalho, Tania M.

In: Cellular Physiology and Biochemistry, Vol. 28, No. 5, 2011, p. 997-1008.

Research output: Contribution to journalArticle

Richter, Claus Peter ; Münscher, Adrian ; Santana MacHado, Danielle ; Wondisford, Fredric E. ; Ortiga-Carvalho, Tania M. / Complete activation of thyroid hormone receptor β by T 3 is essential for normal cochlear function and morphology in mice. In: Cellular Physiology and Biochemistry. 2011 ; Vol. 28, No. 5. pp. 997-1008.
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AU - Wondisford, Fredric E.

AU - Ortiga-Carvalho, Tania M.

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