Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation.
Thyroid hormone (T3) has widespread functions in development and homeostasis, although the receptor pathways by which this diversity arises are unclear. Deletion of the T3 receptors TRalpha1 or TRbeta individually reveals only a small proportion of the phenotypes that arise in hypothyroidism, implying that additional pathways must exist. Here, we demonstrate that mice lacking both TRalpha1 and TRbeta (TRalpha1(-/-)beta-/-) display a novel array of phenotypes not found in single receptor-deficient mice, including an extremely hyperactive pituitary-thyroid axis, poor female fertility and retarded growth and bone maturation. These results establish that major T3 actions are mediated by common pathways in which TRalpha1 and TRbeta cooperate with or substitute for each other. Thus, varying the balance of use of TRalpha1 and TRbeta individually or in combination facilitates control of an extended spectrum of T3 actions. There was no evidence for any previously unidentified T3 receptors in TRalpha1(-/-)beta-/- mouse tissues. Compared to the debilitating symptoms of severe hypothyroidism, the milder overall phenotype of TRalpha1(-/-)beta-/- mice, lacking all known T3 receptors, indicates divergent consequences for hormone versus receptor deficiency. These distinctions suggest that T3-independent actions of T3 receptors, demonstrated previously in vitro, may be a significant function in vivo.
Göthe
S
S
Laboratory of Developmental Biology, CMB, Karolinska Institute, Stockholm, S-17 177, Sweden.
Wang
Z
Z
Ng
L
L
Kindblom
J M
JM
Barros
A C
AC
Ohlsson
C
C
Vennström
B
B
Forrest
D
D
D000367:Age Factors; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000033:anatomy & histology / Q000502:physiology; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility; D006130:Growth Disorders; D007037:Hypothyroidism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D010641:Phenotype; D010902:Pituitary Gland / Q000002:abnormalities* / Q000033:anatomy & histology; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D013961:Thyroid Gland / Q000002:abnormalities* / Q000033:anatomy & histology; D013997:Time Factors
D011988:Receptors, Thyroid Hormone