Title |
Overcoming Monocarboxylate Transporter 8 (MCT8)-Deficiency to Promote Human Oligodendrocyte Differentiation and Myelination
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Published in |
EBioMedicine, October 2017
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DOI | 10.1016/j.ebiom.2017.10.016 |
Pubmed ID | |
Authors |
Jae Young Lee, Min Joung Kim, Devy Deliyanti, Michael F. Azari, Fernando Rossello, Adam Costin, Georg Ramm, Edouard G. Stanley, Andrew G. Elefanty, Jennifer L. Wilkinson-Berka, Steven Petratos |
Abstract |
Cell membrane thyroid hormone (TH) transport can be facilitated by the monocarboxylate transporter 8 (MCT8), encoded by the solute carrier family 16 member 2 (SLC16A2) gene. Human mutations of the gene, SLC16A2, result in the X-linked-inherited psychomotor retardation and hypomyelination disorder, Allan-Herndon-Dudley syndrome (AHDS). We posited that abrogating MCT8-dependent TH transport limits oligodendrogenesis and myelination. We show that human oligodendrocytes (OL), derived from the NKX2.1-GFP human embryonic stem cell (hESC) reporter line, express MCT8. Moreover, treatment of these cultures with DITPA (an MCT8-independent TH analog), up-regulates OL differentiation transcription factors and myelin gene expression. DITPA promotes hESC-derived OL myelination of retinal ganglion axons in co-culture. Pharmacological and genetic blockade of MCT8 induces significant OL apoptosis, impairing myelination. DITPA treatment limits OL apoptosis mediated by SLC16A2 down-regulation primarily signaling through AKT phosphorylation, driving myelination. Our results highlight the potential role of MCT8 in TH transport for human OL development and may implicate DITPA as a promising treatment for developmentally-regulated myelination in AHDS. |
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Science communicators (journalists, bloggers, editors) | 2 | 40% |
Mendeley readers
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Student > Ph. D. Student | 10 | 17% |
Researcher | 9 | 15% |
Student > Doctoral Student | 4 | 7% |
Student > Master | 4 | 7% |
Other | 9 | 15% |
Unknown | 13 | 22% |
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Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
Other | 6 | 10% |
Unknown | 19 | 32% |