Monocarboxylate Transporter 8 in Neuronal Cell Growth
James, S. R., Franklyn, J. A., Reaves, B. J., Smith, V. E., Chan, S. Y., Barrett, T. G., Kilby, M. D. and McCabe, C. J., 2009. Monocarboxylate Transporter 8 in Neuronal Cell Growth. Endocrinology, 150 (4), pp. 1961-1969.
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Thyroid hormones 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 thyroid hormone 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 (WT) MCT8, and the previously reported L471P mutant, on the growth and function of human neuronal precursor NT2 cells as well as MCT8-null JEG-3 cells. HA-tagged WT MCT8 correctly localized to the plasma membrane in NT2 cells and increased T-3 uptake in both cell types. In contrast, L471P MCT8 was largely retained in the endoplasmic reticulum and displayed no T3 transport activity. Transient overexpression of WT and mutant MCT8 proteins failed to induce endoplasmic reticular stress or apoptosis. However, MCT8 overexpression significantly repressed cell proliferation in each cell type in both the presence and absence of the active thyroid hormone T3 and in a dose-dependent manner. In contrast, L471P MCT8 showed no such influence. Finally, small interfering RNA 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. (Endocrinology 150: 1961-1969, 2009)
|Creators||James, S. R., Franklyn, J. A., Reaves, B. J., Smith, V. E., Chan, S. Y., Barrett, T. G., Kilby, M. D. and McCabe, C. J.|
|Departments||Faculty of Science > Biology & Biochemistry|
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