Functional Interference between Thyroid Hormone Receptor α (TRα) and Natural Truncated TRΔα Isoforms in the Control of Intestine Development

Abstract

Thyroid hormone is known to participate in the control of intestine maturation at weaning. Its action is mediated by the thyroid hormone nuclear receptors, encoded by the TRα andTRβ genes. Since previous studies have shown thatTRβ plays a minor role in the gut, we focused here our analysis on the TRα gene. The TRα locus generates the TRα1 receptor together with the splicing variant TRα2 and the truncated products TRΔα1 and TRΔα2, which all lack an intact ligand binding domain. The TRΔα isoforms are transcribed from an internal promoter located in intron 7, and their distribution is restricted to a few tissues including those of the intestine. In order to define the functions of the different isoforms encoded by the TRα locus in the intestinal mucosa, we produced mice either lacking all known TRα products or harboring a mutation which inactivates the intronic promoter. We performed a detailed analysis of the intestinal phenotypes in these mice and compared it to that of the previously described TRα^−/− mice, in which TRα isoforms are abolished but the TRΔα isoforms remain. This comparative analysis leads us to the following conclusions: (i) the TRα1 receptor mediates the T3-dependent functions in the intestine at weaning time and (ii) the TRΔα products negatively control the responsiveness of the epithelial cells to T3. Moreover, we show that TRΔα proteins can interfere with the transcription of the intestine-specific homeobox genes cdx1 and cdx2and that their activity is regulated by TRα1. Altogether these data demonstrate that cooperation of TRα and TRΔα products is essential to ensure the normal postnatal development of the intestine and that mutations in the TRα locus can generate different phenotypes caused by the disruption of the equilibrium between these products.

ACKNOWLEDGMENTS

We warmly thank Claude Legrand and Aude Conscience for their expert technical help and Denise Aubert, who manages the transgenic facility at ENS Lyon. We thank D. Belgarbi and C. Morin for animal breeding. We thank Thomas Lamonerie for providing the plasmid containing the loxP flanked selection cassette and the Cre expression vector. We also thank F. Flamant and M. Kedinger for critical reading of the manuscript.

This work was supported by grants from the Association pour la Recherche contre le Cancer and Région Rhône-Alpes (grant no. 700006058) and by a grant from Human Frontier Scientific Program (fellowship RG0347/1999.M). C.D.D. was a recipient of a fellowship from la Fondation Ipsen.