Endocrine Abstracts

Inactivation of the thyroid hormone transporters Mct8/Oatp1c1 in mice causes a profound TH deficiency in the CNS due to an impaired TH transport across brain barrier cells. As oligodendrocyte maturation and myelin formation requires proper thyroid hormone (TH) signaling, Mct8/Oatp1c1 double knock-out (DKO) mice exhibit a persistent state of hypomyelination similar to the situation in MCT8 deficient patients. Yet, to which extent proper myelination is dependent on the presence of Mct8 and Oatp1c1 in oligodendrocytes and/or their precursor cells has not been determined. Here, we studied myelination at different time points in Mct8/Oatp1c1 mutant mice that lack both transporters only in oligodendroglia cells (= OL CKO mice). For that purpose, conditional Mct8/Oatp1c1 mouse mutants were crossed with transgenic mice expressing cre-recombinase under the control of the oligodendroglia specific Olig2 promoter. OL CKO mice were phenotypically indistinguishable from their cre-negative control littermates and showed normal body weight and locomotor performance as assessed by beam walk and hanging wire test at the age of 4 months. Likewise, serum TH parameters as well as hypothalamic TRH expression were not altered. Analysis of the oligodendrocyte markers MBP and CNPase in the cerebral cortex of 4 months old animals revealed similar immunofluorescence signal intensities in OL CKO and control mice. However, at postnatal day P12, expression of both proteins was found to be significantly reduced in OL CKO mice suggesting a transient delay in myelination. Quantification of mature oligodendrocyte numbers by Olig2/CC1 co-immunostaining at P12 disclosed reduced numbers of double positive cells in OL CKO similar to DKO mice indicating a myelination defect in both mouse models. Altogether, our studies confirm an oligodendrocyte differentiation impairment in the absence of Mct8 and Oatp1c1. The comparison between DKO and OL CKO mice, with OL CKO mice still being able to sense local TH concentrations and only showing a transient delay in myelination, points to cell-autonomous and non-cell-autonomous impacts of both TH transporters. Ongoing studies are expected to disclose at which time points during development Mct8 and Oatp1c1 are required to ensure a normal commitment of precursor cells to the oligodendroglial lineage.