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Updated: Sep 24, 2026
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
[Physiology and pathophysiology of thyroid hormone receptors: the contributions of murine models]
V Vlaeminck-Guillem1, J L Wemeau
1Service de Médecine Interne et Endocrinologie, Clinique Endocrinologique Marc Linquette, CHRU de Lille, 59037 Lille cedex, France.
Abstract:
Thyroid hormones are involved in vertebrate development and metabolic homeostasis. Their actions are mediated through several nuclear receptors encoded by TRalpha and TRB genes. The interspecies conservation of 3 functional receptors (TRalpha1, TRB1 and TRB2) and their partially distinct tissue distribution suggest that they serve non-redundant physiological functions. The exclusive TRB gene involvement in the resistance to thyroid hormone (RTH) reinforces the hypothesis of a functional specificity. Recent mouse knock-out and transgenesis methods allow invalidation or overexpression of a gene of interest, respectively. They therefore provide powerful means to determine the specific function of a gene and have been applied to the thyroid hormone receptor genes. Mice TRB(-/-) represent a model of the recessive form of RTH. They have been shown to develop goiter and high thyroid hormone and TSH (Thyroid Stimulating Hormone) levels, suggesting an unique role for TRB in the negative regulation of TSH pituitary secretion. The associated disorder in audition maturation also showed that TRB plays an essential role in the development of audition. By contrast, mice TRalpha(-/-) exhibited thyroid gland atrophy along with decreased thyroid hormones and TSH levels. Clinical phenotype included growth interruption and retardation of both intestine and bone maturation, but no hearing loss. Mice TRalphaB(-/-) combined the disorders, including delayed neonatal development despite hyperactive hypothalamus-pituitary axis. Finally, transgenic overexpression of a mutant TRB gene reproduced the dominant form of RTH and confirmed the major role of dominant negative activity in the occurrence of some phenotypic key-features such as high circulating hormone levels despite high TSH levels, hyperactivity and lack of severe hearing loss. From these studies, it is suggested that TRalpha and TRB receptors are to some extent able to cooperate or substitute for each other. However some organs constitute TR-specific T3 target-tissues such as inner ear, pituitary, heart, liver, bone and small intestine.
Insights
Thyroid hormone receptors TRalpha and TRB have distinct roles in development and metabolism. Mouse models reveal TRB is crucial for hearing and TSH regulation, while TRalpha impacts growth and bone maturation.
Area of Science:
- Endocrinology and Molecular Biology
- Genetics and Genomics
- Developmental Biology
Context:
- Thyroid hormones regulate critical physiological processes, including development and metabolism.
- Thyroid hormone actions are mediated by nuclear receptors encoded by TRalpha and TRB genes.
- Distinct tissue distribution of TRalpha1, TRB1, and TRB2 suggests non-redundant functions.
Purpose:
- To elucidate the specific physiological functions of thyroid hormone receptors (TRalpha and TRB) using mouse knockout and transgenic models.
- To investigate the roles of TRalpha and TRB in metabolic homeostasis, development, and disease, particularly resistance to thyroid hormone (RTH).
Summary:
- TRB knockout mice exhibit goiter, elevated thyroid hormone and TSH levels, and impaired auditory development, indicating TRB's role in TSH regulation and hearing.
- TRalpha knockout mice show thyroid atrophy, reduced hormone/TSH levels, growth defects, and delayed maturation, but normal hearing.
- Combined TRalpha and TRB deficiency leads to developmental delays, while TRB overexpression models dominant RTH, highlighting receptor-specific functions and interactions.
Impact:
- These findings clarify the specialized roles of TRalpha and TRB in vertebrate physiology, identifying specific target tissues like the inner ear, pituitary, and liver.
- Understanding these distinct functions is crucial for diagnosing and potentially treating thyroid hormone-related disorders, including RTH.
- The study provides a foundation for further research into TR-mediated signaling pathways and their therapeutic implications.
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