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

Thyroid hormone receptors are encoded by the TR alpha (NR1A1) and TR beta (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 TR alpha locus have led to strikingly different phenotypes. In order to analyze the molecular basis for these alterations, rye generated mice devoid of all known isoforms produced from the TR alpha locus (TR alpha (0/0)). These mice are viable and exhibit reduced linear growth, bone maturation delay, moderate hypothermia, and reduced thickness of the intestinal mucosa. Compounding TR alpha (0) and TR beta (-) mutations produces viable TR alpha (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 TR alpha (0/0) and the previously described TR alpha (-/-) mice, which retain truncated TR Delta alpha isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TR alpha (-/-) mice are rescued in TR alpha (0/0) animals. We demonstrate that the TR Delta alpha protein isoforms, which are natural products of the TR alpha locus, are the key determinants of these phenotypical differences. These data reveal the functional importance of the non-T3-binding variants encoded by the TR alpha locus in vertebrate postnatal development and homeostasis.