Characterization of a novel thyroid hormone receptor alpha variant involved in the regulation of myoblast differentiation.
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 TRalpha (NR1A1) and TRbeta (NR1A2) genes. Several TRalpha variants have already been characterized, but only some of them display T3 binding activity. In this study, we have identified another transcript, TRalpha-DeltaE6, 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 TRalpha-DeltaE6 transcript is detected in all mouse tissues tested. Although TRalpha-DeltaE6 did not bind DNA, its expression induced a TRalpha1 sequestration in the cytoplasm. Functional studies demonstrated that TRalpha-DeltaE6 inhibits the transcriptional activity of TRalpha1 and retinoic X receptor-alpha, but not of retinoic acid receptor-alpha. We also found that TRalpha-DeltaE6 efficiently decreased the ability of TRalpha to inhibit MyoD transcriptional activity during myoblast proliferation. Consequently, when overexpressed in myoblasts, it stimulated terminal differentiation. We suggest that this novel TRalpha variant may act as down regulator of overall T3 receptor activity, including its ability to repress MyoD transcriptional activity during myoblast proliferation.
Casas
François
F
Unité Mixte de Recherche-866 Différenciation Cellulaire et Croissance, Institut National de la Recherche Agronomique, Université Montpellier II-Ecole Nationale Supérieure Agronomique, 34060 Montpellier Cedex 1, France. casasf@ensam.inra.fr
Busson
Muriel
M
Grandemange
Stéphanie
S
Seyer
Pascal
P
Carazo
Angel
A
Pessemesse
Laurence
L
Wrutniak-Cabello
Chantal
C
Cabello
Gérard
G
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002645:Chickens; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D014644:Genetic Variation; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism*; D011784:Quail; D011817:Rabbits; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism*; D014018:Tissue Distribution
D018076:DNA, Complementary; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D037021:Thyroid Hormone Receptors alpha