What is it about?

Most of our knowledge on the mechanisms of thyroid hormone (TH) dependent brain development is based on clinical observations and animal studies of maternal/fetal hypothyroidism. THs play an essential role in brain development and hormone deficiency during critical phases in fetal life may lead to severe and permanent brain damage. Maternal hypothyroidism is considered the most common cause of fetal TH deficiency, but the problem may also arise in the fetus. In the case of congenital hypothyroidism due to defects in fetal thyroid gland development or hormone synthesis, clinical symptoms at birth are often mild as a result of compensatory maternal TH supply. TH transporters (THTs) and deiodinases (Ds) are important regulators of intracellular triiodothyronine (T3) availability and therefore contribute to the control of thyroid receptors (TRs)-dependent CNS development and early embryonic life. Defects in fetal THTs or Ds may have more impact on fetal brain since they can result in intracellular T3 deficiency despite sufficient maternal TH supply. One clear example is the recent discovery of mutations in the TH transporter (monocarboxylate transporter 8; MCT8) that could be linked to a syndrome of severe and non reversible psychomotor retardation. Even mild and transient changes in maternal TH levels can directly affect and alter the gene expression profile, and thus disturb fetal brain development. Animal studies are needed to increase our understanding of the exact role of THTs and Ds in prenatal brain development.

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Why is it important?

The fetal dependence on maternal T4 is due (i) to the late development of the fetal thyroid gland (in rodents thyroid function begins by E17–18 and in humans by the 18–20 gestational week) and (ii) to the increased activity of D2 and D3 in placenta and fetal tissues. As a consequence of the increased activity of Ds in the fetus, serum T3 levels are maintained low and the local generation of cerebral T3 from T4 is enhanced. To respond to this requirement, there is an estrogen-dependent increase of maternal thyroid function that transiently induces an increase of (i) circulating thyroxine-binding globulin, affecting the T4 extra-thyroidal pool, and of (ii) human chorionic gonadotropin, transiently stimulating thyrocytes. This increased maternal thyroid function consequently needs increased iodine intake. In the general population, even small variations in maternal thyroid function during pregnancy may affect the developing head of the young child.

Perspectives

From the information above it is clear that THTs and Ds are expressed in brain in a region- and cell specific way. It is also clear that deficiencies in THTs or Ds can adversely affect neurodevelopment but the neurological phenotypes are far from understood. The defects are partly different from the ones observed due to fetal hypothyroidism and the phenotype can also differ between humans and rodents. It seems therefore essential to extend the research in two directions, towards earlier developmental stages and towards other model species. Additional research in different models using conditional silencing will hopefully further improve our understanding on how THTs, Ds and TRs cooperate to regulate TR-mediated impact on vertebrate CNS development.

Full Professor Ahmed R. G.
Division of Anatomy and Embryology, Zoology department, Faculty of Science, Beni-Suef University, Egypt.

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This page is a summary of: Hypothyroidism and brain developmental players, Thyroid Research, February 2015, Springer Science + Business Media,
DOI: 10.1186/s13044-015-0013-7.
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