Genetic analysis reveals different functions for the products of the thyroid hormone receptor alpha locus.

Abstract:

: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(0/0)beta(-/-) 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 TRDeltaalpha 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 TRDeltaalpha 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.

journal_name

Mol Cell Biol

authors

Gauthier K,Plateroti M,Harvey CB,Williams GR,Weiss RE,Refetoff S,Willott JF,Sundin V,Roux JP,Malaval L,Hara M,Samarut J,Chassande O

doi

10.1128/MCB.21.14.4748-4760.2001

subject

Has Abstract

pub_date

2001-07-01 00:00:00

pages

4748-60

issue

14

eissn

0270-7306

issn

1098-5549

journal_volume

21

pub_type

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