Thyroid hormone transport into the brain

TOPIC: Role of membrane transporters of thyroid hormone on their transfer into the brain

Title: Expression of the thyroid hormone transporter MCT8 (SLC16A2) and AOTP14 (SLC01C1) at the blood-brain barrier.

Authors: Roberts LM, Woodford K, Zhou M, Black DS, et al.

Reference: Endocrinology 149: 6251-6261, 2008



Thyroid hormones require transport across cell membranes in order to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human MCT8 transporter (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that MCT8 expression in the mouse brain is restricted to neurons, leading to the model that OATP14 (OATP1C1, SLCO1C1) is the primary thyroid hormone transporter at the blood brain barrier, while MCT8 mediates thyroid hormone uptake into neurons.


In contrast to these previous reports, the authors report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein was strongly enriched in mouse and rat cerebral microvessels, but not in human microvessels. In rat, MCT8 and OATP14 proteins localize to both the luminal and abluminal microvessel membranes. In human and rodent choroid plexus epithelial cells, MCT8 is concentrated on the epithelial cell apical surface and OATP14 localizes primarily to the basal-lateral surface. MCT8 and OATP14 expression was also observed in mouse and rat tanycytes, which are thought to form a barrier between hypothalamic blood vessels and brain.


These results raise the possibility that reduced thyroid hormone transport across the blood-brain barrier contributes to the neurological deficits observed in affected patients with MCT8 mutations. The high microvessel expression of OATP14 in rodent compared to human brain may contribute to the relatively mild phenotype observed in MCT8-null mice, in contrast to humans lacking functional MCT8.


Mutations in the MCT8 gene, located on the X-chromosome, have been recently identified in humans. The clinical presentation of these patients has two components, a thyroid and a neuropsychiatric aspect. Characteristic thyroid function test abnormalities encompass an increase in serum T3 and decreased reverse T3 concentrations. Serum T4 is reduced in most cases and TSH is normal or slightly elevated. Severe psychomotor retardation, observed in hemizygous affected males, includes truncal hypotonia, spastic quadriplegia, absent speech, severe mental retardation and in some cases paroxysmal dyskinesia and seizures. Mice deficient in MCT8 ( MCT8 Knock Outs ) replicate the thyroid function abnormalities observed in man while showing no obvious neurological abnormality. This raises the possibility that the psychomotor defect in humans may not be solely due to thyroid hormone (TH) deficiency in brain at a crucial time of development, but also to other factors, such as the transport by MCT8 of other ligands essential for normal human brain development. However, up to date, studies have failed to demonstrate that MCT8 transports substances other than TH.

Roberts et al. studied the presence of MCT8 and the alternative thyroid hormone transporter (OATP14) in the brains of mice, rats & humans. The authors showed that OATP14, expressed in a high level at the blood brain barrier (cerebral micro-vessels) of rodents, is only present at very low levels in humans. This work suggests that the alternative route of TH transport, partially correcting TH deficiency in mice that lack functional MCT8, is sufficient to prevent the manifestations of the neurological phenotype observed in humans. Summary and Commentary prepared by Sam Refetoff (Related to Chapter 3 of TDM)

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