Athyroid Pax8-/- mice cannot be rescued by the inactivation of thyroid hormone receptor alpha1.
The Pax8(-/-) mouse provides an ideal animal model to study the consequences of congenital hypothyroidism, because its only known defect is the absence of thyroid follicular cells. Pax8(-/-) mice are, therefore, completely athyroid in postnatal life and die around weaning unless they are substituted with thyroid hormones. As reported recently, Pax8(-/-) mice can also be rescued and survive to adulthood by the additional elimination of the entire thyroid hormone receptor alpha (TRalpha) gene, yielding Pax8(-/-)TRalpha(o/o) double-knockout animals. This observation has led to the hypothesis that unliganded TRalpha1 might be responsible for the lethal phenotype observed in Pax8(-/-) animals. In this study we report the generation of Pax8(-/-)TRalpha1(-/-) double-knockout mice that still express the non-T(3)-binding TR isoforms alpha2 and Deltaalpha2. These animals closely resemble the phenotype of Pax8(-/-) mice, including growth retardation and a completely distorted appearance of the pituitary with thyrotroph hyperplasia and hypertrophy, extremely high TSH mRNA levels, reduced GH mRNA expression, and the almost complete absence of lactotrophs. Like Pax8(-/-) mice, Pax8(-/-)TRalpha1(-/-) compound mutants die around weaning unless they are substituted with thyroid hormones. These findings do not support the previous interpretation that the short life span of Pax8(-/-) mice is due to the negative effects of the TRalpha1 aporeceptor, but, rather, suggest a more complex mechanism involving TRalpha2 and an unliganded TR isoform.
Mittag
Jens
J
Max Planck Institut für Experimentelle Endokrinologie, Feodor Lynen Strasse 7, D-30625 Hannover, Germany.
Friedrichsen
Sönke
S
Heuer
Heike
H
Polsfuss
Silke
S
Visser
Theo J
TJ
Bauer
Karl
K
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005260:Female; D007037:Hypothyroidism / Q000097:blood / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency*; D009929:Organ Size; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010907:Pituitary Hormones / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013961:Thyroid Gland / Q000002:abnormalities* / Q000473:pathology; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency* / Q000378:metabolism; D013970:Thyronines / Q000097:blood; D015534:Trans-Activators / Q000172:deficiency*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D010907:Pituitary Hormones; D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D013970:Thyronines; D015534:Trans-Activators