Monocarboxylate transporter 8 (MCT8) in neuronal cell growth

SR James, Jayne Franklyn, BJ Reaves, Vicki Smith, Shiao-yng Chan, Timothy Barrett, Mark Kilby, Christopher McCabe

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Thyroid hormones (THs) are essential for the normal growth and development of the fetus, and even small alterations in maternal thyroid hormone status during early pregnancy may be associated with neurodevelopmental abnormalities in childhood. Mutations in the novel and specific TH transporter monocarboxylate transporter 8 (MCT8) have been associated with severe neurodevelopmental impairment. However, the mechanism by which MCT8 influences neural development remains poorly defined. We have therefore investigated the effect of wild type MCT8, and the previously reported L471P mutant, upon the growth and function of human neuronal precursor NT2 cells, as well as MCT8-null JEG-3 cells. HA-tagged WT MCT8 correctly localised to the plasma membrane in NT2 cells and increased T3 uptake in both cell types. In contrast, L471P MCT8 was largely retained in the endoplasmic reticulum, and displayed no T3 transport activity. Transient over-expression of wild type and mutant MCT8 proteins failed to induce endoplasmic reticular (ER) stress or apoptosis. However, MCT8 over-expression significantly repressed cell proliferation in each cell type, both in the presence and absence of the active thyroid hormone tri-iodothyronine (T3), and in a dose-dependent manner. In contrast, L471P MCT8 showed no such influence. Finally, siRNA depletion of endogenous MCT8 resulted in increased cell survival and decreased T3 uptake. Given that T3 stimulated proliferation in embryonic neuronal NT2 cells, whereas MCT8 repressed cell growth, these data suggest an entirely novel role for MCT8 in addition to T3 transport, mediated through the modulation of cell proliferation in the developing brain.
Original languageEnglish
Pages (from-to)1961-1969
Number of pages9
JournalEndocrinology
Volume150
Issue number4
DOIs
Publication statusPublished - 20 Nov 2008

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