Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis
Open accessAbstract
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.
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OATP1C1 transporter transports T4 thyroid hormone.
“Hormone endothelial transporters include MCT8 transporter for T3 (triiodothyronine) thyroid hormone and the organic anion transporting polypeptide 1c1 (OATP1C1) transporter for T 4 (thyroxine) thyroid hormone (396, 502).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [396]
MCT8 transporter transports T3 thyroid hormone.
“Hormone endothelial transporters include MCT8 transporter for T3 (triiodothyronine) thyroid hormone and the organic anion transporting polypeptide 1c1 (OATP1C1) transporter for T 4 (thyroxine) thyroid hormone (396, 502).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [396]
Murine Mct8 regulates the transport of T3 across the BBB.
“Murine Mct8 regulates the transport of T3 across the BBB (Ceballos et al., 2009; Mayerl et al., 2014)”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Mayerl et al., 2014
Mct8/Oatp1c1 double KO displayed a severe form of CNS-specific hypothyroidism, including decreased myelination and abnormal neuronal differentiation.
“the Mct8/Oatp1c1 double KO displayed a severe form of CNS-specific hypothyroidism, including decreased myelination and abnormal neuronal differentiation (Mayerl et al., 2014).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Mayerl et al., 2014
These results align with reduced synaptophysin expression in post-mortem human brain and neuronal deficiencies in Mct8/Oatp1c1 dKO mouse and zebrafish Mct8 mutant.
“These results align with several findings in MCT8 deficiency, including reduced synaptophysin expression in the post-mortem human brain (López-Espíndola et al., 2014) and neuronal deficiencies observed in the Mct8/Oatp1c1 double KO (dKO) mouse (Mayerl et al., 2014) and zebrafish Mct8 mutant model (Zada et al., 2014).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Mayerl et al., 2014
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- Authors
- Mayerl, S., Müller, J., Bauer, R., Richert, S., Kassmann, C. M., Darras, V. M., Buder, K., Boelen, A., Visser, T. J., & Heuer, H.
- Affiliations
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Jena University Hospital (DE)
- Max Planck Society (DE)
- KU Leuven (BE)
- Amsterdam UMC Location University of Amsterdam (NL)
- Erasmus MC (NL)
- Leibniz Institute of Environmental Medicine (DE)
- Corresponding author
- Heuer, Heike
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2014-04-01
- Volume
- 124
- Issue
- 5
- Pages
- 1987-1999
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4001533
- OpenAlex
- W2046037386
- Cited by
- 281
- References
- 6
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 20 · 2023: 20 · 2022: 26 · 2021: 25 · 2020: 21 · 2019: 32 · 2018: 16 · 2017: 30 · 2016: 25 · 2015: 24 · 2014: 12
- FWCI
- 24.41
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Friedrich-Schiller-Universität Jena (RTG 1715)
- Deutsche Forschungsgemeinschaft (RTG1715, HE3418/5-1, SPP1629, HE 3418/7-1)
- Erasmus Medisch Centrum
- KU Leuven
- Leibniz-Gemeinschaft
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- MCT8, OATP1C1, thyroid hormone transport, Allan-Herndon-Dudley syndrome, blood-brain barrier, triiodothyronine, thyroxine, deiodinase activity, brain development, cerebellar development, myelination, cerebral cortex, thyroid hormone homeostasis
- MeSH terms
- Animals, Cerebral Cortex, Homeostasis, Muscle Hypotonia, Muscular Atrophy, Nerve Tissue Proteins, Thyroxine, Triiodothyronine, Mice, Knockout, Membrane Transport Proteins, Monocarboxylic Acid Transporters, Organic Cation Transport Proteins, Symporters, X-Linked Intellectual Disability, Mental Retardation, X-Linked, Mice, GABAergic Neurons
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