Endocrine Abstracts

The thyroid hormone (TH) transporters Mct8 (encoded by Slc16a2) and Oatp1c1 (encoded by Slco1c1) are critically involved in mediating TH passage across mouse brain barrier cells. Mct8/Oatp1c1 deficient mice (= DKO mice) exhibit a strongly reduced brain TH content and consequently, an impaired neuronal development and hypomyelination all of which are also seen in patients with MCT8 deficiency (Allan-Herndon-Dudley Syndrome, AHDS). Our recent studies of mouse mutants lacking both TH transporters specifically in blood-brain-barrier (BBB) endothelial cells (= Endo del mice) underscore the physiological relevance of Mct8/Oatp1c1 in facilitating TH access to the CNS. yet, these Endo del mice showed a much milder phenotype compared to DKO animals pointing to additional pathogenic CNS events in global Mct8/Oatp1c1 deficiency that still needs to be unraveled. We considered a hitherto unknown function of both TH transporters in brain angiogenesis and therefore examined brain capillary network formation in wildtype, single and double TH transporter knockout mice. For this, we performed immunoflurescence stainings of brain vibratome sections using the endothelial vascular marker CD31. Quantification of vessel parameters was conducted using the open-source software ‘VesselExpress’. While vessel parameters at postnatal day P6 were similar in all experimental groups, quantification of cortical vessel length and branching at P12 revealed an almost 50% reduction in DKO mice. Single TH transporter mutant mice were not affected. Brain vessel rarefaction was also observed at P21 and P120 in DKO mice. Moreover, comparing the total vessel lengths of capillaries with different diameter revealed a significantly reduced total length only of DKO capillaries with a diameter less than 10 µm. Of note, while Oatp1c1 is ubiquitously found in all brain endothelial cells under physiological conditions, Mct8 is preferentially expressed by CNS endothelial cells of small capillaries suggesting that this subgroup of endothelial cells is particularly impacted by combined Mct8/Oatp1c1 deficiency. We further quantified the transcript levels of different capillary proteins in dissected brain areas of four months old animals and confirmed reduced CD31, Vegfa as well as glucose transporter Glut1 mRNA expression in DKO mice. Altogether, our observation of a reduced microcapillay network in DKO mice that potentially compromises local oxygen and/or nutrient supply may thus add novel insights into the pathogenic mechanisms underlying human MCT8 deficiency. (Study is financially supported by DFG and embedded in CRC/TR296-P01, P09, P19)