Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis
Steffen Mayerl, … , Theo J. Visser, Heike Heuer
Steffen Mayerl, … , Theo J. Visser, Heike Heuer
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):1987-1999. https://doi.org/10.1172/JCI70324.
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Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis

Abstract

Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of Mct8 (Mct8 KO) faithfully replicates AHDS-associated endocrine abnormalities; however, unlike patients, these animals do not exhibit neurological impairments. While transport of the active form of TH (T3) across the blood-brain barrier is strongly diminished in Mct8 KO animals, prohormone (T4) can still enter the brain, possibly due to the presence of T4-selective organic anion transporting polypeptide (OATP1C1). Here, we characterized mice deficient for both TH transporters, MCT8 and OATP1C1 (Mct8/Oatp1c1 DKO). Mct8/Oatp1c1 DKO mice exhibited alterations in peripheral TH homeostasis that were similar to those in Mct8 KO mice; however, uptake of both T3 and T4 into the brains of Mct8/Oatp1c1 DKO mice was strongly reduced. Evidence of TH deprivation in the CNS of Mct8/Oatp1c1 DKO mice included highly decreased brain TH content as well as altered deiodinase activities and TH target gene expression. Consistent with delayed cerebellar development and reduced myelination, Mct8/Oatp1c1 DKO mice displayed pronounced locomotor abnormalities. Intriguingly, differentiation of GABAergic interneurons in the cerebral cortex was highly compromised. Our findings underscore the importance of TH transporters for proper brain development and provide a basis to study the pathogenic mechanisms underlying AHDS.

Authors

Steffen Mayerl, Julia Müller, Reinhard Bauer, Sarah Richert, Celia M. Kassmann, Veerle M. Darras, Katrin Buder, Anita Boelen, Theo J. Visser, Heike Heuer

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Figure 6

Mct8/Oatp1c1 DKO mice display reduced myelination.

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Mct8/Oatp1c1 DKO mice display reduced myelination. (A) Frontal vibrat...
(A) Frontal vibratome brain sections of male animals (n = 3 per genotype and time point) were stained with FluoroMyelin (FM), a dye that incorporates into myelin sheaths. Additionally, consecutive sections were stained with an antibody against MBP. Quantification of the fluorescence signal densities revealed reduced staining in Mct8/Oatp1c1 DKO mice at all time points (P12, P33, and P120). Scale bar: 600 μm. (B) Ultrathin sections of the medial part of the cc were analyzed by electron microscopy at P21 (n = 3). Compared with WT animals, the number of myelinated axons was visibly decreased in Mct8/Oatp1c1 DKO mice as well as in athyroid Pax8 KO mice. However, the ultrastructure of the myelin sheaths appeared rather similar in all genotypes (higher-magnification insets). Scale bars: 5 μm (top); 500 nm (bottom); 50 nm (insets). (C) P21 and P180 coronal paraffin brain sections subjected to Gallyas silver staining were used to quantify cc thickness at the cingulum bundle (n = 3). Only Mct8/Oatp1c1 DKO mice showed decreased cc thickness at either time point. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT, or as otherwise indicated (brackets).