Endocrine Abstracts

Impaired TH transport across brain barriers results in severe TH deficiency in Mct8/Oatp1c1 DKO mice, leading to disturbed neuronal development, myelination as well as locomotor abnormalities. Although brain-barrier associated cells (i.e. endothelial cells, astrocytes, choroid plexus epithelial cells) have been shown to express both transporters, the cell-specific function of Mct8 and Oatp1c1 has still not been defined. Here, we generated and analysed mouse mutants that lack Mct8 and Oatp1c1 in endothelial cells only (= Endo del mice). For that purpose, conditional Mct8/Oatp1c1 flox animals were crossed with mice expressing Cre-recombinase under the constitutively active Tek2 promoter (= Tie2 cre). Endo del mice were born at the expected mendelian frequency and phenotypically indistinguishable from their control littermates. Immunofluorescence studies confirmed a cell-specific deletion of Mct8 in brain capillary endothelial cells while expression of Mct8 in choroid plexus, tanycytes as well as in neurons was not affected. Mct8 expression was also preserved in peripheral tissues such as liver and heart of Endo del mice. Immunofluorescence analysis of Endo del mice at postnatal day P12 revealed a strongly reduced number of inhibitory Parvalbumin-positive neurons in the cerebral cortex, similarly to the phenotype seen in global Mct8/Oatp1c1 deficiency. In contrast, myelination was less compromised in Endo del animals compared to global Mct8/Oatp1c1 DKO mice. Fluorescence in situ hybridization studies were conducted at the age of 4 months and revealed increased TRH expression in the paraventricular hypothalamic nucleus (PVN) similarly to the increase seen in DKO mice. Likewise, hybridization signal intensities for the TH regulated genes RC3, Klf9, Aldh1a1 showed decreased levels in Endo del mice as well as in DKO mice. Altogether, our data point to a sustained TH-deficient CNS in Endo del mice and thus underscore the critical role of Mct8 and Oatp1c1 in mediating TH transport across endothelial cells.