The T3Ralpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production

Abstract

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.

The history of a developmental stage: Metamorphosis in chordates

“…Sexual maturity does not qualify as metamorphosis either since it is regulated by steroids and is often asynchronous with metamorphosis. On the contrary, mammalian weaning gathers all characteristics of metamorphosis as defined above as a period of tissue remodeling governed by TH (Fraichard et al, 1997). Indeed, it is an ecological shift that is characterized by modifications like neural maturation, intestine remodeling, or chondrogenesis that are reminiscent of similar events during amphibian metamorphosis.…”

Effects of T3Rα1 and T3Rα2 Gene Deletion on T and B Lymphocyte Development

“…T3R␣ KO mice, developed on the outbred OF 1 background, were generated in our laboratory (19). All mice were bred in the institute's animal facility and kept under pathogen-free conditions.…”

“…T3R␣ (19)-, T3R␤ (20)-, and T3R␣1 (21)-deficient mice have recently been generated by targeted gene disruption. The T3R␣ KO mice are deficient for the T3R␣1 and T3R␣2 isoforms (19). However, they are still able to express the T3R⌬␣1 and T3R⌬␣2 short transcripts (22), which function is unknown.…”

“…These mice have a general growth defect and die between 4 -6 wk of age. A number of defaults, including bone and small intestine development, have been investigated (19).…”

Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERRα

“…We reasoned that if ERRa up-regulates the endogenous TRa, then both receptors should be present in certain tissues. Indeed, data collected in the literature indicate that TRa and ERRa are found together in some organs (GigueÁ re et al, 1988;Forrest et al, 1990;Strait et al, 1990;Bonnelye et al, 1997b;Sladek et al, 1997;Fraichard et al, 1997). To evaluate tissue coexpression of both receptors, we performed in situ hybridizations of mouse embryonic or adult adjacent sections with probes corresponding to either ERRa or TRa.…”