Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis
Steffen Mayerl, Julia Müller, Reinhard Bauer, Sarah Richert, Celia M. Kassmann, Veerle M. Darras, Katrin Buder, Anita Boelen, Theo J. Visser, Heike Heuer
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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Research Article Neuroscience

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 5

Consequences of combined MCT8 and OATP1C1 deficiency on T3 target gene expression in the CNS.

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Consequences of combined MCT8 and OATP1C1 deficiency on T3 target gene e...
(A) ISH studies performed using brain sections at P21 (n = 4 per genotype) revealed for Mct8/Oatp1c1 DKO mice a strong downregulation in the signal intensities for Hr, RC3, and Aldh1a1, all known to be positively regulated by T3. Hr expression was most prominently decreased throughout the cerebral cortex, whereas RC3 expression was highly reduced in neurons of the striatum. In cortical areas, Aldh1a1-specific ISH signals were specifically reduced in astrocytes, but relatively unaltered in capillary endothelial cells. Darkfield autoradiograms also illustrated upregulation of D2 in glial cells. Interestingly, mRNA expression of Crym, an intracellular TH binding protein, was elevated specifically in the cortex and striatum. Scale bar: 600 μm (Hr, RC3, Aldh1a1, and D2); 3 mm (Crym). (B) qPCR analysis was performed using forebrain homogenates from P21 animals (n = 4–5 per genotype). Athyroid Pax8 KO mice were included and showed changes in forebrain gene expression similar to those of Mct8/Oatp1c1 DKO mice. These findings again pointed to a TH-deprived CNS in the absence of MCT8 and OATP1C1. *P < 0.05, **P < 0.01, ***P < 0.001 vs. WT.