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Characterization of a Novel Thyroid Hormone Receptor Variant Involved in the Regulation of Myoblast Differentiation

Unité Mixte de Recherche-866 Différenciation Cellulaire et Croissance [Institut National de la Recherche Agronomique (INRA)-Université Montpellier II-Ecole Nationale Supérieure Agronomique de Montpellier], INRA, 34060 Montpellier Cedex 1, France

Address all correspondence and requests for reprints to: François Casas, Unité Mixte de Recherche-866 Différenciation Cellulaire et Croissance, Institut National de la Recherche Agronomique (INRA), 2 place Viala, 34060 Montpellier Cedex 1, France. E-mail: casasf{at}ensam.inra.fr.

The regulation of gene expression by thyroid hormone (T₃) involves binding of the hormone to nuclear receptors [thyroid hormone receptor (TR)] acting as T₃-dependent transcription factors encoded by TR (NR1A1) and TRß (NR1A2) genes. Several TR variants have already been characterized, but only some of them display T₃ binding activity. In this study, we have identified another transcript, TR-E6, produced by alternative splicing with microexon 6b instead of exon 6. This splicing leads to the synthesis of a protein devoid of a hinge domain. The TR-E6 transcript is detected in all mouse tissues tested. Although TR-E6 did not bind DNA, its expression induced a TR1 sequestration in the cytoplasm. Functional studies demonstrated that TR-E6 inhibits the transcriptional activity of TR1 and retinoic X receptor-, but not of retinoic acid receptor-. We also found that TR-E6 efficiently decreased the ability of TR to inhibit MyoD transcriptional activity during myoblast proliferation. Consequently, when overexpressed in myoblasts, it stimulated terminal differentiation. We suggest that this novel TR variant may act as down regulator of overall T₃ receptor activity, including its ability to repress MyoD transcriptional activity during myoblast proliferation.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RXRα

Ligands:   all-trans-Retinoic acid  |  9-cis-Retinoic acid  |  Thyroid hormone

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