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Published on: March 14, 2017
Congenital hypothyroid Pax8(-/-) mutant mice can be rescued by inactivating the TRalpha gene
Frédéric Flamant1, Anne-Lise Poguet, Michelina Plateroti
1Laboratoire de Biologie Moléculaire et Cellulaire de l'Ecole Normale Supérieure de Lyon, Unité Mixte de Recherche Centre National de la Recherche Scientifique 5665 LA INRA913, 69364 Lyon Cedex 07, France. Frederic.Flamant@ens-lyon.fr
Abstract:
Mice devoid of all TRs are viable, whereas Pax8(-/-) mice, which lack the follicular cells producing T4 and T3 in the thyroid gland, die during the first weeks of postnatal life. A precise comparison between the two types of mutants reveals that their phenotypes are similar, but the defects in spleen, bone, and small intestine are more pronounced in Pax8(-/-) mice. This is interpreted as the result of a negative effect of the unliganded TR on thyroid hormone target genes expression in the Pax8(-/-) mutants. Pax8/TRalpha compound mutants can survive to adulthood, and the expression of target genes is partially restored. This demonstrates the importance of TRalpha aporeceptor activity in several aspects of postnatal development.
Insights
Mice lacking thyroid hormone receptors (TRs) or thyroid follicular cells (Pax8-/-) show developmental defects. The absence of TRalpha aporeceptor activity exacerbates these issues, highlighting its crucial role in postnatal development.
Area of Science:
- Endocrinology
- Developmental Biology
- Molecular Genetics
Background:
- Thyroid hormones (T4 and T3) are essential for postnatal development.
- Thyroid hormone receptors (TRs) mediate the effects of thyroid hormones.
- Pax8 is crucial for thyroid follicular cell development and hormone production.
Purpose of the Study:
- To compare the developmental phenotypes of mice lacking all TRs versus those lacking thyroid follicular cells (Pax8-/-).
- To investigate the role of TRalpha aporeceptor activity in postnatal development.
Main Methods:
- Generation and analysis of mice models: TR-null mice, Pax8-/- mice, and Pax8/TRalpha compound mutants.
- Phenotypic comparison focusing on spleen, bone, and small intestine development.
- Assessment of thyroid hormone target gene expression.
Main Results:
- Pax8-/- mice exhibit developmental defects, including lethality, more pronounced than TR-null mice.
- Unliganded TRs in Pax8-/- mice negatively impact thyroid hormone target gene expression.
- Pax8/TRalpha compound mutants survive to adulthood with partially restored gene expression.
Conclusions:
- TRalpha aporeceptor activity is critical for multiple aspects of postnatal development.
- The interaction between TRs and thyroid hormone production is essential for normal development.
- Thyroid hormone signaling pathways are complex and involve both liganded and unliganded receptor functions.
