title: The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N-Tera-2 neurodifferentiation.
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.
authors.affiliation: School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Floor 3, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK. s.chan@bham.ac.uk
authors.forename: S-Y
authors.initials: SY
authors.lastname: Chan
authors.forename: A
authors.initials: A
authors.lastname: Martín-Santos
authors.forename: L S
authors.initials: LS
authors.lastname: Loubière
authors.forename: A M
authors.initials: AM
authors.lastname: González
authors.forename: B
authors.initials: B
authors.lastname: Stieger
authors.forename: A
authors.initials: A
authors.lastname: Logan
authors.forename: C J
authors.initials: CJ
authors.lastname: McCabe
authors.forename: J A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: M D
authors.initials: MD
authors.lastname: Kilby
mesh_terms: D037881:Aborted Fetus / Q000196:embryology / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000235:genetics; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000196:embryology* / Q000378:metabolism; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics; D027261:Fusion Regulatory Protein-1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005865:Gestational Age; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D016900:Neurofilament Proteins / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D027981:Symporters; D013963:Thyroid Hormones / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D027182:Amino Acid Transport System y+; D026921:Amino Acid Transport Systems, Neutral; D002352:Carrier Proteins; D027301:Fusion Regulatory Protein 1, Light Chains; D027261:Fusion Regulatory Protein-1; D007381:Intermediate Filament Proteins; D027283:Large Neutral Amino Acid-Transporter 1; D027501:Monocarboxylic Acid Transporters; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D016900:Neurofilament Proteins; D050814:Octamer Transcription Factor-3; D027361:Organic Anion Transporters; C494173:POU5F1 protein, human; D034741:RNA, Small Interfering; C498964:SLC16A10 protein, human; C090735:SLC16A2 protein, human; C420646:SLC7A8 protein, human; D027981:Symporters; D013963:Thyroid Hormones; D014284:Triiodothyronine; D014212:Tretinoin