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Athyroid Pax8^–/– Mice Cannot Be Rescued by the Inactivation of Thyroid Hormone Receptor 1

Max Planck Institute for Experimental Endocrinology (J.M., S.P., K.B.), D-30625 Hannover, Germany; Department of Medicine, University of Manchester (S.F.), Manchester M13 9PT, United Kingdom; Institut für Molekulare Biotechnologie (H.H.), D-07745 Jena, Germany; and Department of Internal Medicine, Erasmus University Medical Center (T.J.V.), NL-3000 DR Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. Karl Bauer, Max Planck Institut für Experimentelle Endokrinologie, Feodor Lynen Strasse 7, D-30625 Hannover, Germany. E-mail: karl.bauer{at}mpihan.mpg.de.

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 (TR) gene, yielding Pax8^–/–TR^o/o double-knockout animals. This observation has led to the hypothesis that unliganded TR1 might be responsible for the lethal phenotype observed in Pax8^–/– animals. In this study we report the generation of Pax8^–/–TR1^–/– double-knockout mice that still express the non-T₃-binding TR isoforms 2 and 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^–/–TR1^–/– 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 TR1 aporeceptor, but, rather, suggest a more complex mechanism involving TR2 and an unliganded TR isoform.

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