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 8

Abnormal gait and severe locomotor deficiencies in Mct8/Oatp1c1 DKO mice.

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Abnormal gait and severe locomotor deficiencies in Mct8/Oatp1c1 DKO mice...
Mct8/Oatp1c1 DKO animals exhibited abnormal gait, as demonstrated by significantly reduced stride length (A), and a strongly elevated hind paw angle (B) based on footprint analysis. (C) Locomotor deficiencies were monitored by a rotarod test using 4-month-old male mice (n = 6–8 per genotype). In contrast to WT, Mct8 KO, and Oatp1c1 KO animals, Mct8/Oatp1c1 DKO mice performed poorly on the rod and did not show a learning curve. #P < 0.001 vs. WT. (D) In order to assess balance and coordination, mice were monitored while running on a beam 1 cm wide and 100 cm long. Recording the hind limb slips revealed a significantly higher number of errors only in Mct8/Oatp1c1 DKO mice. (E) Mice were further subjected to a hanging wire test in order to determine neuromuscular abnormalities. Only Mct8/Oatp1c1 DKO mice were not able to cling on a metal wire for 60 seconds. (F) As these findings point to reduced muscle performance, forepaw muscle strength was quantified using a grip strength meter, revealing an approximately 35% reduction in Mct8/Oatp1c1 DKO animals. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT, or as otherwise indicated (brackets).