Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

doi:10.1073/pnas.0401843101

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

^*Animage-Rhône Alpes Genopole, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5515, 59 Boulevard Pinel, 69003 Lyon, France; ^†Department of Diagnostic Imaging, Ecole Nationale Vétérinaire de Lyon, 1 Avenue Bourgelat, BP 83, 69280 Marcy l'Etoile, France; ^‡Laboratoire de Biologie Moléculaire de la Cellule, Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche, Centre National de la Recherche Scientifique 5161, Institut National de la Recherche Agronomique 1237, Institut Fédératif de Recherche 128 Biosciences Lyon-Gerland, 46 Allée d'Italie, 69364 Lyon Cedex 07, France; and ^§Université Claude Bernard Lyon I, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France

Edited by Donald D. Brown, Carnegie Institution of Washington, Baltimore, MD, and approved May 7, 2004 (received for review March 16, 2004)

Abstract

Thyroid hormones are involved in the regulation of many physiological processes and regulate gene transcription by binding to their nuclear receptors TRα and TRβ. In the absence of triiodothyronine (T3), the unliganded receptors (aporeceptors) do bind DNA and repress the transcription of target genes. The role of thyroid hormone aporeceptors as repressors was observed in hypothyroid adult mice, but its physiological relevance in nonpathological hypothyroid conditions remained to be determined. Here we show that, in the normal mouse fetus, TRα aporeceptors repress heart rate as well as the expression of TRβ and several genes encoding ion channels involved in cardiac contractile activity. Right after birth, when T3 concentration sharply increases, liganded TRα (holoreceptors) turn on the expression of some of these same genes concomitantly with heart rate increase. These data describe a physiological situation under which conversion of TRα from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: jacques.samarut{at}ens-lyon.fr.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: TH, thyroid hormone; T3, triiodothyronine; TR, TH receptor; HR, heart rate; pc, postcoitum; P18, 18-day-old pups; A11, 11-wk-old adult mice; E15.5 fetuses, 15.5-day-old fetuses.