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. IntroductionMonocarboxylate transporter 8 (MCT8) is a specific thyroid hormone (TH) transporter that facilitates the passage of the prohormone 3,3′,5,5′-tetraiodothyronine (T4; also known as thyroxine) and the receptor active form, 3,3′,5-triiodothyronine (T3), across the plasma membrane (1). MCT8 is encoded by SLC16A2 (hereafter MCT8) located on human chromosome Xq13.2. Inactivating mutations and deletions in MCT8 result in a distinct clinical picture known as Allan-Herndon-Dudley syndrome (AHDS) (2-5).All affected patients manifest a severe form of psychomotor retardation composed of central hypotonia, spastic tetraplegia, lack of speech development, severe intellectual deficits, and global developmental delays. In addition to the pronounced neurological symptoms, patients exhibit characteristic changes in the serum TH profile, with highly elevated T3 and lowered T4 concentrations. Since 2004, more than 45 families with 125 affected individuals have been reported in the literature, and 1% of cases with the diagnosis of X-linked mental retardation have been estimated to be associated with mutations in MCT8 (6). However, by which pathogenic mechanisms MCT8 deficiency causes AHDS remains largely unknown.MCT8 is present in many organs, such as liver, kidneys, pituitary, and thyroid gland, and is also widely expressed in the CNS. Studies in mouse and human brain tissues revealed MCT8 expression in distinct neuronal populations, with the highest mRNA levels in neo-and allocortical structures (e.g., cerebral cor...

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

“…In mice, however, apart from phenocopying the altered serum TH profile, Mct8 knockout (KO) results in an apparently unaffected cerebellar structure (Trajkovic et al 2007, Koibuchi 2009, coupled with normal performance in locomotor behavioural tests (Wirth et al 2009). The differences between those animal models are likely to be explained by the presence of additional TH transporters, such as organic anion transporting polypeptide 1C1 (OATP1C1) (Mayerl et al 2014) and large type amino acid transporter 2 (LAT2) (Wirth et al 2009, Nunez et al 2014) that can compensate for the reduced TH uptake at the rodent blood-brain barrier and neuronal membrane, respectively. Correspondingly, Mct8/Oatp1c1 double KO mice display neurological and locomotor deficits, which can be attributed to impaired TH transport across the blood-brain barrier (Fu et al 2013, Mayerl et al 2014.…”

“…The differences between those animal models are likely to be explained by the presence of additional TH transporters, such as organic anion transporting polypeptide 1C1 (OATP1C1) (Mayerl et al 2014) and large type amino acid transporter 2 (LAT2) (Wirth et al 2009, Nunez et al 2014) that can compensate for the reduced TH uptake at the rodent blood-brain barrier and neuronal membrane, respectively. Correspondingly, Mct8/Oatp1c1 double KO mice display neurological and locomotor deficits, which can be attributed to impaired TH transport across the blood-brain barrier (Fu et al 2013, Mayerl et al 2014. However, this model is less appropriate to assess the in vivo role of MCT8 at the level of the neurons themselves.…”

The Hypothyroid Brain

“…There are other families of TH transporters, such as the organic anion-transporting polypeptide (OATP) family, of which OATP1C1 is an important representative, encoded by the gene SLCO1C1, and L-type amino acid transporter (LAT), which is represented by LAT1 and LAT2 and transcribed by SLC7A5 and SLC7A8 genes, respectively [93] .…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…Members of the OATP family are involved in the transport of bilirubin (OATP1B1 and OATP1B3) and thyroid hormones (OATP1C1) (Keppler, 2014;Mayerl et al, 2014). In the liver, bilirubin metabolism and elimination is accomplished, in part, by the coordinated actions of OATPs and UDP glucuronosyltransferase-1 family, polypeptide-1.…”

“…OATPs also may be involved in transporting endogenous substances that are otherwise impermeant and cannot traverse the cell membrane passively and, therefore, rely on transporters to enter cells. OATP1C1 has been implicated recently in the transport across the blood-brain barrier of thyroxine, the prohormone of triiodothyronine, a process thought to be important for proper brain development (Mayerl et al, 2014). The physiologic and pharmacological importance of renal OATPs, particularly the role of OATP4C1, is not fully appreciated.…”