Functional interference between thyroid hormone receptor alpha (TRalpha) and natural truncated TRDeltaalpha isoforms in the control of intestine development.
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 TRalpha and TRbeta genes. Since previous studies have shown that TRbeta plays a minor role in the gut, we focused here our analysis on the TRalpha gene. The TRalpha locus generates the TRalpha1 receptor together with the splicing variant TRalpha2 and the truncated products TRDeltaalpha1 and TRDeltaalpha2, which all lack an intact ligand binding domain. The TRDeltaalpha 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 TRalpha locus in the intestinal mucosa, we produced mice either lacking all known TRalpha 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 TRalpha(-/-) mice, in which TRalpha isoforms are abolished but the TRDeltaalpha isoforms remain. This comparative analysis leads us to the following conclusions: (i) the TRalpha1 receptor mediates the T3-dependent functions in the intestine at weaning time and (ii) the TRDeltaalpha products negatively control the responsiveness of the epithelial cells to T3. Moreover, we show that TRDeltaalpha proteins can interfere with the transcription of the intestine-specific homeobox genes cdx1 and cdx2 and that their activity is regulated by TRalpha1. Altogether these data demonstrate that cooperation of TRalpha and TRDeltaalpha products is essential to ensure the normal postnatal development of the intestine and that mutations in the TRalpha locus can generate different phenotypes caused by the disruption of the equilibrium between these products.
Plateroti
M
M
Laboratoire de Biologie Moléculaire et Cellulaire de l'ENS de Lyon, UMR 5665 CNRS, LA 913 INRA, 69364 Lyon Cedex 07, France.
Gauthier
K
K
Domon-Dell
C
C
Freund
J N
JN
Samarut
J
J
Chassande
O
O
D000818:Animals; D030161:Avian Proteins; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D002455:Cell Division; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000254:growth & development* / Q000473:pathology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators; D014284:Triiodothyronine / Q000378:metabolism
D030161:Avian Proteins; C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C491272:Cdx1 protein, mouse; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D015534:Trans-Activators; D014284:Triiodothyronine