S. Gothe et al., Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation, GENE DEV, 13(10), 1999, pp. 1329-1341
Thyroid hormone (T3) has widespread functions in development and homeostasi
s, although the receptor pathways by which this diversity arises are unclea
r. Deletion of the T3 receptors TR alpha 1 or TR beta individually reveals
only a small proportion of the phenotypes that arise in hypothyroidism, imp
lying that additional pathways must exist. Here, we demonstrate that mice l
acking both TR alpha 1 and TR beta (TR alpha 1(-/-)beta(-/-)) display a nov
el array of phenotypes not found in single receptor-deficient mice, includi
ng an extremely hyperactive pituitary-thyroid axis, poor female fertility a
nd retarded growth and bone maturation. These results establish that major
T3 actions are mediated by common pathways in which TR alpha 1 and TR beta
cooperate with or substitute for each other. Thus, varying the balance of u
se of TR alpha 1 and TR beta individually or in combination facilitates con
trol of an extended spectrum of T3 actions. There was no evidence for any p
reviously unidentified T3 receptors in TR alpha 1(-/-)beta(-/-) mouse tissu
es. Compared to the debilitating symptoms of severe hypothyroidism, the mil
der overall phenotype of TR alpha 1(-/-)beta(-/-) mice, lacking all known T
3 receptors, indicates divergent consequences for hormone versus receptor d
eficiency. These distinctions suggest that T3-independent actions of T3 rec
eptors, demonstrated previously in vitro, may be a significant function in
vivo.