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This version published online on March 31, 2005
Endocrinology, doi:10.1210/en.2005-0114
A more recent version of this article appeared on July 1, 2005
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Submitted on January 31, 2005
Accepted on March 22, 2005

Athyroid Pax8-/- Mice Cannot be Rescued by the Inactivation of Thyroid Hormone Receptor TR{alpha}1

Jens Mittag, Sönke Friedrichsen, Heike Heuer, Silke Polsfu{beta}, Theo J. Visser, and Karl Bauer*

Max Planck Institute for experimental Endocrinology, Hannover, Germany (J.M., S.P., K.B.); University of Manchester, Dept. Medicine, England (S.F.); Institut für Molekulare Biotechnologie, Jena, Germany (H.H.); Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands (T.J.V.)

* To whom correspondence should be addressed. E-mail: karl.bauer{at}mpihan.mpg.de.

The Pax8-/- mouse provides an ideal animal model to study the consequences of congenital hypothyroidism since 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 TR{alpha} gene, yielding Pax8-/-TR{alpha}o/o double knockout animals. This observation has led to the hypothesis that unliganded TR{alpha}1 might be responsible for the lethal phenotype observed in Pax8-/- animals.

Here we report the generation of Pax8-/-TR{alpha}1-/- double knockout mice which still express the non T3-binding TR isoforms {alpha}2 and {Delta}{alpha}2. 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-/-TR{alpha}1-/- compound mutants die around weaning unless they are substituted with thyroid hormones. These findings do not support the previous interpretation that the short lifespan of Pax8-/- mice is due to the negative effects of the TR{alpha}1 aporeceptor but rather suggest a more complex mechanism involving TR{alpha}2 and an unliganded TR isoform.
Key words: Pituitary Hormones • Iodothyronine Deiodinase D1 • Congenital Hypothyroidism




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