Thyroid Hormone Receptor α1 Directly Controls Transcription of the β-Catenin Gene in Intestinal Epithelial Cells

Abstract

Thyroid hormones, T3 and T4, are known regulators of intestine development. The best characterized example is the remodeling of the gastrointestinal tract during amphibian metamorphosis. Thyroid hormones act via nuclear receptors, the TRs, which are T3-dependent transcription factors. We previously showed that intestinal epithelial cell proliferation is controlled by thyroid hormones and the TRα gene. To analyze the mechanisms responsible, we studied the expression of genes belonging to and/or activated by the Wnt/β-catenin pathway, a major actor in the control of physiological and pathological epithelial proliferation in the intestine. We show that T3-TRα1 controls the transcription of the β-catenin gene in an epithelial cell-autonomous way. This is parallel to positive regulation of proliferation-controlling genes such as type D cyclins and c-myc, known targets of the Wnt/β-catenin. In addition, we show that the regulation of the β-catenin gene is direct, as TR binds in vitro and in chromatin in vivo to a specific thyroid hormone-responsive element present in intron 1 of this gene. This is the first report concerning in vivo transcriptional control of the β-catenin gene. As Wnt/β-catenin plays a crucial role in intestinal tumorigenesis, our observations open a new perspective on the study of TRs as potential tumor inducers.

Supplemental material for this article may be found at http://mcb.asm.org.

We thank the animal (PBES) and microscopy (PLATIM) facilities of the IFR 128 Biosciences. We also thank the ANIGENE platform of Rhône-Alpes Génopole. We gratefully acknowledge Nadine Aguilera for animal handling. We thank N. Davidson, K. Gauthier, and B. Pain for critical reading of the manuscript and O. Bakker for help in immunolabeling for TRα1.We are grateful to A. Rezza for participation in experiments with adult animals.

This work was supported by a grant from the Ligue Nationale contre le Cancer to J.S. (Equipe Labellisée). E.K. was a fellow of the Ligue Nationale contre le Cancer.