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Characterization of a novel thyroid hormone receptor alpha variant involved in the regulation of myoblast differentiation
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Edité par CCSD ; Endocrine Society -
International audience. The regulation of gene expression by thyroid hormone (T-3) involves binding of the hormone to nuclear receptors [ thyroid hormone receptor (TR)] acting as T-3-dependent transcription factors encoded by TR alpha (NR1A1) and TR beta (NR1A2) genes. Several TR alpha variants have already been characterized, but only some of them display T-3 binding activity. In this study, we have identified another transcript, TR alpha-Delta 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 alpha-Delta E6 transcript is detected in all mouse tissues tested. Although TR alpha-Delta E6 did not bind DNA, its expression induced a TR alpha 1 sequestration in the cytoplasm. Functional studies demonstrated that TR alpha-Delta E6 inhibits the transcriptional activity of TR alpha 1 and retinoic X receptor-alpha, but not of retinoic acid receptor-alpha. We also found that TR alpha-Delta E6 efficiently decreased the ability of TR alpha to inhibit MyoD transcriptional activity during myoblast proliferation. Consequently, when overexpressed in myoblasts, it stimulated terminal differentiation. We suggest that this novel TR alpha variant may act as down regulator of overall T-3 receptor activity, including its ability to repress MyoD transcriptional activity during myoblast proliferation.
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