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Molecular and Cellular Biology, July 2001, p. 4748-4760, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4748-4760.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Genetic Analysis Reveals Different Functions for the Products of the Thyroid Hormone Receptor alpha  Locus

Karine Gauthier,1 Michelina Plateroti,1 Clare B. Harvey,2 Graham R. Williams,2 Roy E. Weiss,3 Samuel Refetoff,3,4 James F. Willott,5 Victoria Sundin,6 Jean-Paul Roux,7 Luc Malaval,7 Masahiro Hara,1 Jacques Samarut,1,* and Olivier Chassande1

Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure, UMR 5665 CNRS, LA 913 INRA, 69364 Lyon cedex 07,1 and INSERM U369, Faculté de médecine, RTH Laennec, Lyon,7 France; ICSM Molecular Endocrinology Group, Division of Medicine and MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom2; Departments of Medicine3 and Pediatrics,4 University of Chicago, Chicago, Illinois 60637; Department of Psychology, University of South Florida, Tampa, Florida 336205; and Department of Psychology, Northern Illinois University, Dekalb, Illinois 601156

Received 27 November 2000/Returned for modification 13 February 2001/Accepted 15 April 2001

Thyroid hormone receptors are encoded by the TRalpha (NR1A1) and TRbeta (NR1A2) loci. These genes are transcribed into multiple variants whose functions are unclear. Analysis by gene inactivation in mice has provided new insights into the functional complexity of these products. Different strategies designed to modify the TRalpha locus have led to strikingly different phenotypes. In order to analyze the molecular basis for these alterations, we generated mice devoid of all known isoforms produced from the TRalpha locus (TRalpha 0/0). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRalpha 0 and TRbeta - mutations produces viable TRalpha 0/0beta -/- mice, which display a more severe linear growth reduction and a more profound hypothermia as well as impaired hearing. A striking phenotypic difference is observed between TRalpha 0/0 and the previously described TRalpha -/- mice, which retain truncated TRDelta alpha isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TRalpha -/- mice are rescued in TRalpha 0/0 animals. We demonstrate that the TRDelta alpha protein isoforms, which are natural products of the TRalpha locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the TRalpha locus in vertebrate postnatal development and homeostasis.

* Corresponding author. Mailing address: Laboratoire de Biologie Moléculaire et Cellulaire, CNRS UMR 5665 ENS LA 913 INRA, Ecole Normale Supérieure, 46 allée d'Italie, 69364 Lyon Cedex 07, France. Phone: 33 4 72 72 81 71. Fax: 33 4 72 72 85 36. E-mail: Jacques.Samarut{at}enslyon.fr.

Molecular and Cellular Biology, July 2001, p. 4748-4760, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4748-4760.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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