Abstract
Thyroid hormone receptors are encoded by the
TRα
(NR1A1) and
TRβ
(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
TRα
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
TRα
locus (TRα
0/0
). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRα
0
and TRβ
−
mutations produces viable TRα
0/0
β
−/−
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 TRα
0/0
and the previously described TRα
−/−
mice, which retain truncated TRΔα isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TRα
−/−
mice are rescued in TRα
0/0
animals. We demonstrate that the TRΔα protein isoforms, which are natural products of the
TRα
locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the
TRα
locus in vertebrate postnatal development and homeostasis.
