Samuel Refetoff

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

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 (TRα0/0). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRα0 and TRβ− mutations produces viable TRα0/0β−/− 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 TRα0/0 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 TRα0/0animals. 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 theTRα locus in vertebrate postnatal development and homeostasis.