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Thyroid hormone receptors in brain development and function

Abstract

Thyroid hormones are important during development of the mammalian brain, acting on migration and differentiation of neural cells, synaptogenesis, and myelination. The actions of thyroid hormones are mediated through nuclear thyroid hormone receptors (TRs) and regulation of gene expression. The purpose of this article is to review the role of TRs in brain maturation. In developing humans maternal and fetal thyroid glands provide thyroid hormones to the fetal brain, but the timing of receptor ontogeny agrees with clinical data on the importance of the maternal thyroid gland before midgestation. Several TR isoforms, which are encoded by the THRA and THRB genes, are expressed in the brain, with the most common being TRα1. Deletion of TRα1 in rodents is not, however, equivalent to hormone deprivation and, paradoxically, even prevents the effects of hypothyroidism. Unliganded receptor activity is, therefore, probably an important factor in causing the harmful effects of hypothyroidism. Accordingly, expression of a mutant receptor with impaired triiodothyronine (T3) binding and dominant negative activity affected cerebellar development and motor performance. TRs are also involved in adult brain function. TRα1 deletion, or expression of a dominant negative mutant receptor, induces consistent behavioral changes in adult mice, leading to severe anxiety and morphological changes in the hippocampus.

Key Points

  • Thyroid hormones are important in brain development by regulating cell migration and differentiation, synaptogenesis, and myelination

  • The early steps of embryonic neural development, such as neural induction, neurulation, and establishment of polarity and segmentation, are probably not influenced by thyroid hormones

  • Deficient production of maternal thyroid hormones during the first half of gestation may lead to neurological deficits and is a primary factor in the pathogenesis of neurological cretinism

  • Gene regulation by thyroid hormones in brain follows a strict temporal and regional specificity; most genes are sensitive only during a limited time period of postnatal development, and some genes are under thyroid hormone control only in certain brain regions

  • Some of the morphological alterations induced by profound hypothyroidism might actually be a consequence of the altered transcriptional activity of unliganded receptors; receptor deletion is therefore not equivalent to hormone deprivation

  • Unlike deletion of the thyroid hormone receptor, expression of dominant negative receptors produces a phenotype more similar to the hypothyroid phenotype

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Figure 1: Control of gene expression by the TR
Figure 2: A summary of human fetal and postnatal brain development in relation to thyroid hormones

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Acknowledgements

I have been supported by grant BFU2005-01740 from the Ministry of Education and Science, Spain, and by the European Union Integrated Project LSHM-CT-2005-018652, CRESCENDO (Consortium for Research into Nuclear Receptors in Development and Aging).

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Bernal, J. Thyroid hormone receptors in brain development and function. Nat Rev Endocrinol 3, 249–259 (2007). https://doi.org/10.1038/ncpendmet0424

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