The diverse functions of thyroid hormones are thought to be mediated by two nuclear receptors, T3Rα1 and T3Rβ, encoded by the genes T3Rα and T3Rβ respectively. The T3Rα gene also produces a non‐ligand‐binding protein T3Rα2. The in vivo functions of these receptors are still unclear. We describe here the homozygous inactivation of the T3Rα gene which abrogates the production of both T3Rα1 and T3Rα2 isoforms and that leads to death in mice within 5 weeks after birth. After 2 weeks of life, the homozygous mice become progressively hypothyroidic and exhibit a growth arrest. Small intestine and bones showed a strongly delayed maturation. In contrast to the negative regulatory function of the T3Rβ gene on thyroid hormone production, our data show that the T3Rα gene products are involved in up‐regulation of thyroid hormone production at weaning time. Thus, thyroid hormone production might be balanced through a positive T3Rα and a negative T3Rβ pathway. The abnormal phenotypes observed on the homozygous mutant mice strongly suggest that the T3Rα gene is essential for the transformation of a mother‐dependent pup to an ‘adult’ mouse. These data define crucial in vivo functions for thyroid hormones through a T3Rα pathway during post‐natal development.

Thyroid hormone receptors are encoded by the TR␣ (NR1A1) and TR␤ (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␣ 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 TR␣ locus (TR␣ 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␣ 0 and TR␤ ؊ mutations produces viable TR␣ 0/0 ␤ ؊/؊ 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␣ 0/0 and the previously described TR␣ ؊/؊ mice, which retain truncated TR⌬␣ isoforms arising from a newly described promoter in intron 7. The lethality and severe impairment of the intestinal maturation in TR␣ ؊/؊ mice are rescued in TR␣ 0/0 animals. We demonstrate that the TR⌬␣ protein isoforms, which are natural products of the TR␣ 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␣ locus in vertebrate postnatal development and homeostasis.

Primary aldosteronism (PA) is the main cause of secondary hypertension, resulting from adrenal aldosterone-producing adenomas (APA) or bilateral hyperplasia. Here, we show that constitutive activation of WNT/β-catenin signalling is the most frequent molecular alteration found in 70% of APA. We provide evidence that decreased expression of the WNT inhibitor SFRP2 may be contributing to deregulated WNT signalling and APA development in patients. This is supported by the demonstration that mice with genetic ablation of Sfrp2 have increased aldosterone production and ectopic differentiation of zona glomerulosa cells. We further show that β-catenin plays an essential role in the control of basal and Angiotensin II-induced aldosterone secretion, by activating AT1R, CYP21 and CYP11B2 transcription. This relies on both LEF/TCF-dependent activation of AT1R and CYP21 regulatory regions and indirect activation of CYP21 and CYP11B2 promoters, through increased expression of the nuclear receptors NURR1 and NUR77. Altogether, these data show that aberrant WNT/β-catenin activation is associated with APA development and suggest that WNT pathway may be a good therapeutic target in PA.

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