title: Lack of action of exogenously administered T3 on the fetal rat brain despite expression of the monocarboxylate transporter 8.
abstract: Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain.
authors.affiliation: Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Grijota-Martínez
authors.forename: Diego
authors.initials: D
authors.lastname: Díez
authors.forename: Gabriella
authors.initials: G
authors.lastname: Morreale de Escobar
authors.forename: Juan
authors.initials: J
authors.lastname: Bernal
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morte
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D027701:Organic Cation Transport Proteins; D051381:Rats; D017208:Rats, Wistar; D013974:Thyroxine / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D026923:Amino Acid Transport Systems, Basic; D047908:Intracellular Signaling Peptides and Proteins; D027501:Monocarboxylic Acid Transporters; D009419:Nerve Tissue Proteins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C526853:Sema3C protein, rat; C105348:Slc7a3 protein, rat; C451262:Slco1c1 protein, rat; C478998:monocarboxylate transporter 8, rat; D014284:Triiodothyronine; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517686:Camk4 protein, rat; D013974:Thyroxine