The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N‐Tera‐2 neurodifferentiation

Abstract

Non-technical summary Thyroid hormones are important in brain development and they enter cells through thyroid hormone transporters at the cell membrane. Thyroid hormone transporters are thought to play an important role since gene defects in one of these transporters, MCT8, have been associated with severe mental retardation. This paper describes the expression of a range of thyroid hormone transporters in the human fetal brain during early pregnancy, and suggests that these transporters could regulate the supply of thyroid hormones into brain cells from very early in development. Surprisingly, the reduction of thyroid hormones and MCT8 expression do not affect the differentiation of an unspecialised cell to a specialised human nerve cell in the brain. Thyroid hormones and MCT8 are thus likely to affect other processes during human brain development. To find out how thyroid hormones influence human fetal brain development requires further research.Abstract Associations of neurological impairment with mutations in the thyroid hormone (TH) transporter, MCT8, and with maternal hypothyroxinaemia, suggest that THs are crucial for human fetal brain development. It has been postulated that TH transporters regulate the cellular supply of THs within the fetal brain during development. This study describes the expression of TH transporters in the human fetal cerebral cortex (7-20 weeks gestation) and during retinoic acid induced neurodifferentiation of the human N-Tera-2 (NT2) cell line, in triiodothyronine (T3) replete and T3-depleted media. Compared with adult cortex, mRNAs encoding OATP1A2, OATP1C1, OATP3A1 variant 2, OATP4A1, LAT2 and CD98 were reduced in fetal cortex at different gestational ages, whilst mRNAs encoding MCT8, MCT10, OATP3A1 variant 1 and LAT1 were similar. From the early first trimester, immunohistochemistry localised MCT8 and MCT10 to the microvasculature and to undifferentiated CNS cells. With neurodifferentiation, NT2 cells demonstrated declining T3 uptake, accompanied by reduced expressions of MCT8, LAT1, CD98 and OATP4A1. T3 depletion significantly reduced MCT10 and LAT2 mRNA expression at specific time points during neurodifferentiation but there were no effects upon T3 uptake, neurodifferentiation marker expression or neurite lengths and branching. MCT8 repression also did not affect NT2 neurodifferentiation. In conclusion, many TH transporters are expressed in the human fetal cerebral cortex from the first trimester, which could regulate cellular TH supply during early development. However, human NT2 neurodifferentiation is not dependent upon T3 or MCT8 and there were no compensatory changes to promote T3 uptake in a T3-depleted environment.

Thyroid hormones in fetal growth and prepartum maturation

“…In adult animals, thyroid hormone transporters have been identified in the liver, kidney, brain, lung, and placenta. In the cerebral cortex of the human fetus at 7-20 weeks of gestation, MCT8 and MCT10 (SLC16A10) mRNA levels are similar to those in the adult brain, and developmental changes in OATP (SLCO1A2) mRNA have been reported (Chan et al 2011). Thyroid hormone transporter proteins in the brain and other tissues are likely to have an important role in determining tissue-specific bioavailability of the thyroid hormones in fetal as well as in adult life.…”

“…The metabolism of T 4 into more genomically potent T 3 or relatively bio-inactive reverse T 3 (rT 3 ) depends on the activity of deiodinase enzymes, which are developmentally regulated in specific tissues (Brent 2012, Table 1 Comparison of the timing of developmental stages of thyroid hormone bioavailability among human, sheep, and rat fetuses. Data adapted from Thorburn & Hopkins (1973), Bernal & Pekonen (1984, Perez-Castillo et al (1985), Ferreiro et al (1987), Polk et al (1989Polk et al ( , 1991, Thorpe-Beeston et al (1991b), Polk (1995), Brown (2004, and Chan et al (2011) et al 2002). D1 is primarily a 5 0 -monodeiodinase enzyme that catalyzes outer-ring deiodination of T 4 to T 3 and of rT 3 to T 2 .…”

Thyroid hormone transporters and deiodinases in the developing human hypothalamus

“…Recently, Chan et al (42) have published that many TH transporters including MCT8, MCT10, and OATP1C1 are also expressed in the human fetal cerebral cortex, which could regulate cellular TH supply during early development (7-20 weeks of gestation). The number of observations in our study is still limited, and therefore, caution should be used when interpreting the results.…”

Thyroid hormone regulated genes in cerebral cortex development

“…Low concentrations of OATP1C1, as it has been shown in the monkey BBB (Ito et al 2011) would make the human brain critically dependent on MCT8 for TH transport. MCT8 protein and mRNA can be detected in the human brain as early as the 7th-8th PMW (Chan et al 2011).…”