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

Shiao-yng Chan, A Martin-Santos, Laurence Loubiere, Ana Gonzalez, B Stieger, Ann Logan, Christopher McCabe, Jayne Franklyn, Mark Kilby

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39 Citations (Scopus)


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.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.
Original languageEnglish
Pages (from-to)2827-2845
Number of pages19
JournalThe Journal of Physiology
Issue number11
Publication statusPublished - 1 Jun 2011


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