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Role of the Thyroid System in Myelination and Neural Connectivity

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ABSTRACT

The role of thyroid hormone on brain development is dramatically illustrated by “cretinism,” a severe mental retardation due to iodine deficiency and maternal hypothyroidism during gestation. In the last decades, the molecular bases of the cellular action of thyroid hormone in the nervous tissue have been at least partially elucidated, and the emerged picture is much more complex than expected. In this article, the main mechanisms determining thyroid hormone availability, nuclear and membrane receptor occupancy and downstream action, gene expression, and nongenomic mechanism are reviewed, focusing on myelination and myelin turnover. © 2015 American Physiological Society. Compr Physiol 5:1405‐1421, 2015.

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Figure 1. Figure 1. The thyroid system in the brain. The Figure represents a schematic scenario of TH transport into—and processing inside—the CNS cells. Blood brain barrier (BBB) is formed by capillary endothelial cells which are connected by tight junctions. T4 and T3 are transported from the blood into the brain through the BBB TH transporters transthyretin, OATP1C1 and MCT8, among others. Inside the brain, T4 can be transported into astrocytes by OATP1C1 and transformed in the active T3 through the enzyme. T3 is transported from the intracellular/interstitial fluid into neurons or OPCs, where can bind TH nuclear receptors (TR) initiating the genomic actions of TH, or can be inactivated by D3 to give T2 or rT3. Integrin αVβ3 binds preferably T4 initiating the nongenomic effects of TH which may also lead to specific changes in gene transcription inside neurons. Abbreviations: TH, thyroid hormone; CNS, central nervous system; OATP1C1, organic anion transporter protein 1C1; MCT8, monocarboxylate anion transporter type 8; MCT10, monocarboxylate anion transporter type 10; D2, deiodinase enzyme type 2; D3, deiodinase enzyme type 3; OPCs, oligodendrocyte precursor cells.
Figure 2. Figure 2. Postnatal development expression of thyroid hormone receptors, deiodinases, transporters, and markers of myelination in the cerebellum. The expression profile of different thyroid hormone signaling components and myelination markers in the cerebellum at different postnatal stages is summarized in the graphs. The gene expression was studied by real‐time PCR whereas protein levels by Western blot. (A) Thyroid hormone receptors (TR) α1, α2, and β1 mRNA. (B) Deiodinases type 2, 3, and the TH transporter MCT8 mRNA. (C) Myelination markers gene expression: precursor oligodendrocytes, Olig‐1, PDGF‐αR; mature oligodendrocytes, MBP. (D) MBP protein 17, 18.5 and 21.5 KDa subunits. C and D are published results (). Results are expressed as mean values ± SEM. Abbreviations: MCT8, monocarboxylate anion transporter type 8; PDGF‐αR, platelet derived growth factor receptor type alpha; MBP, myelin basic protein.


Figure 1. The thyroid system in the brain. The Figure represents a schematic scenario of TH transport into—and processing inside—the CNS cells. Blood brain barrier (BBB) is formed by capillary endothelial cells which are connected by tight junctions. T4 and T3 are transported from the blood into the brain through the BBB TH transporters transthyretin, OATP1C1 and MCT8, among others. Inside the brain, T4 can be transported into astrocytes by OATP1C1 and transformed in the active T3 through the enzyme. T3 is transported from the intracellular/interstitial fluid into neurons or OPCs, where can bind TH nuclear receptors (TR) initiating the genomic actions of TH, or can be inactivated by D3 to give T2 or rT3. Integrin αVβ3 binds preferably T4 initiating the nongenomic effects of TH which may also lead to specific changes in gene transcription inside neurons. Abbreviations: TH, thyroid hormone; CNS, central nervous system; OATP1C1, organic anion transporter protein 1C1; MCT8, monocarboxylate anion transporter type 8; MCT10, monocarboxylate anion transporter type 10; D2, deiodinase enzyme type 2; D3, deiodinase enzyme type 3; OPCs, oligodendrocyte precursor cells.


Figure 2. Postnatal development expression of thyroid hormone receptors, deiodinases, transporters, and markers of myelination in the cerebellum. The expression profile of different thyroid hormone signaling components and myelination markers in the cerebellum at different postnatal stages is summarized in the graphs. The gene expression was studied by real‐time PCR whereas protein levels by Western blot. (A) Thyroid hormone receptors (TR) α1, α2, and β1 mRNA. (B) Deiodinases type 2, 3, and the TH transporter MCT8 mRNA. (C) Myelination markers gene expression: precursor oligodendrocytes, Olig‐1, PDGF‐αR; mature oligodendrocytes, MBP. (D) MBP protein 17, 18.5 and 21.5 KDa subunits. C and D are published results (). Results are expressed as mean values ± SEM. Abbreviations: MCT8, monocarboxylate anion transporter type 8; PDGF‐αR, platelet derived growth factor receptor type alpha; MBP, myelin basic protein.
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Laura Calzà, Mercedes Fernández, Luciana Giardino. Role of the Thyroid System in Myelination and Neural Connectivity. Compr Physiol 2015, 5: 1405-1421. doi: 10.1002/cphy.c140035