Thyroid hormone receptor alpha isoforms generated by alternative splicing differentially activate myosin HC gene transcription.

Thyroid hormones are thought to modulate gene expression positively or negatively through interactions with chromatin-associated receptors. Recently, the c-erb A proto-oncogene products have been shown to be nuclear thyroid hormone (T3) receptors (TR) by sequence similarity with other steroid receptors and by their ability to bind thyroid hormone. But it has not been shown that these receptors directly activate transcription of the responsive genes in vivo. In addition, the rat TR alpha gene encodes several messenger RNA (mRNA) species, generated by differential processing of its transcripts (ref. 22). For these reasons we investigated the ability of two major isoforms of the rat TR alpha gene products to activate transcription of a sarcomeric myosin heavy chain (mHC) gene, because expression of all members of this gene family is responsive to T3. We show here that the rTR alpha 1 receptor is a thyroid hormone-dependent transcriptional factor, which upon binding the T3 responsive element of the alpha-mHC gene, activates expression of this gene in vivo. The rTR alpha 2 isoform, which is identical to rTR alpha 1 except for its carboxyl terminal portion, is generated by alternative splicing of the rTR alpha gene transcript. This peptide, when produced in vitro and in vivo failed to bind T3 or other hormones or to trans-activate alpha-mHC gene expression. Thus, alternative splicing can produce marked differences in the functional properties of a transcriptional factor.