Monocarboxylate transporter 8 in neuronal cell growth.
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 T(3) 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 T(3) 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 T(3) uptake. Given that T(3) stimulated proliferation in embryonic neuronal NT2 cells, whereas MCT8 repressed cell growth, these data suggest an entirely novel role for MCT8 in addition to T(3) transport, mediated through the modulation of cell proliferation in the developing brain.
James
S R
SR
School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Franklyn
J A
JA
Reaves
B J
BJ
Smith
V E
VE
Chan
S Y
SY
Barrett
T G
TG
Kilby
M D
MD
McCabe
C J
CJ
D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D003459:Crystallins / Q000235:genetics; D004721:Endoplasmic Reticulum; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors; D006801:Humans; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D027981:Symporters; D014284:Triiodothyronine / Q000378:metabolism; D000090803:mu-Crystallins
D003459:Crystallins; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D034741:RNA, Small Interfering; C090735:SLC16A2 protein, human; C406962:SLC16A4 protein, human; D027981:Symporters; D014284:Triiodothyronine; D000090803:mu-Crystallins; D053148:Caspase 3; D053179:Caspase 7