Affiliation:
1. Laboratoire de Biologie Moléculaire et Cellulaire de l'ENS de Lyon, UMR 5665 CNRS, LA 913 INRA, 69364 Lyon Cedex 07, 1 and
2. INSERM U.381, 67200 Strasbourg, 2 France
Abstract
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
and
TRβ
genes. Since previous studies have shown that
TRβ
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
cdx2
and 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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
125 articles.
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