The role of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in fetal brain development
SR James1, CJ McCabe1, VE Smith1, SY Chan2, TG Barrett3, JA Franklyn1 & MD Kilby2
Thyroid hormones play a major role in the metabolic function of mammalian cells and are of particular importance in the development of the fetal brain. The MCT8 gene has recently been shown to encode an active and specific thyroid hormone transporter. Recent reports have identified mutations in the MCT8 gene in several unrelated boys presenting with severe X-linked psychomotor retardation and elevated serum T3.
Ontogeny of mRNA encoding MCT8 was examined in 61 human fetal cerebral cortex (from surgical TOP), and 10 normal adult samples (MRC CNS collection, UK). All samples were collected with ethical approval. MCT8 mRNA was detected in the fetal cerebral cortex from as early as 7 weeks gestation and maintained at a similar level through into adulthood.
We transiently transfected N-TERA-2 (NT2) cells (a human embryonal cell line with characteristics of CNS precursor cells) with either wild-type MCT8 or its Leu471Pro mutation, as found in a local patient with severe psychomotor impairment1. Immunofluorescence analysis revealed differential localisation of WT and mutant proteins, the mutant mainly being retained intracellularly and WT showing more intense cell-surface expression.
NT2 cells were also grown in T3 deplete media. Over-expression of both WT and mutant MCT8, alone or in combination, reduced proliferation in the absence of T3 (P<0.05 for WT MCT8 transfection, P<0.01 for mutant or combined transfections). Addition of 10nM T3 had a pro-proliferative effect in control cells (8.3% increase, P<0.001, N=36), which was also observed in cells transfected with WT MCT8. However, over-expression of mutant MCT8, alone or in combination with WT, suppressed proliferation in the presence of T3 (9.8% decrease, P<0.01), indicating a potential alternative role for MCT8 in addition to T3 transport. We therefore propose that disruption of MCT8 fundamentally alters the proliferation of fetal neural cells in the developing brain.
1. Friesema et al., Lancet, 2004.