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

Abstract : Thyroid hormone receptors are encoded by the TRa (NR1A1) and TRb (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 TRa 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 TRa locus (TRa0/0). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TRa0 and TRb2 mutations produces viable TRa0/0b2/2 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 TRa0/0 and the previously described TRa2/2 mice, which retain truncated TRDa isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TRa2/2 mice are rescued in TRa0/0 animals. We demonstrate that the TRDa protein isoforms, which are natural products of the TRa locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3- binding variants encoded by the TRa locus in vertebrate postnatal development and homeostasis.