Abstract
Thyroid hormone entry into cells is facilitated by transmembrane transporters. Mutations of the specific thyroid hormone transporter, MCT8 (Monocarboxylate Transporter 8, SLC16A2) cause an X-linked syndrome of profound neurological impairment and altered thyroid function known as the Allan-Herndon-Dudley syndrome. MCT8 deficiency presumably results in failure of thyroid hormone to reach the neural target cells in adequate amounts to sustain normal brain development. However during the perinatal period the absence of Mct8 in mice induces a state of cerebral cortex hyperthyroidism, indicating increased brain access and/or retention of thyroid hormone. The contribution of other transporters to thyroid hormone metabolism and action, especially in the context of MCT8 deficiency is not clear. We have analyzed the role of the heterodimeric aminoacid transporter Lat2 (Slc7a8), in the presence or absence of Mct8, on thyroid hormone concentrations and on expression of thyroid hormone-dependent cerebral cortex genes. To this end we generated Lat2-/-, and Mct8-/yLat2 -/- mice, to compare with wild type and Mct8-/y mice during postnatal development. As described previously the single Mct8 KO neonates had a transient increase of 3,5,3′-triiodothyronine concentration and expression of thyroid hormone target genes in the cerebral cortex. Strikingly the absence of Lat2 in the double Mct8Lat2 KO prevented the effect of Mct8 inactivation in newborns. The Lat2 effect was not observed from postnatal day 5 onwards. On postnatal day 21 the Mct8 KO displayed the typical pattern of thyroid hormone concentrations in plasma, decreased cortex 3,5,3′-triiodothyronine concentration and Hr expression, and concomitant Lat2 inactivation produced little to no modifications. As Lat2 is expressed in neurons and in the choroid plexus, the results support a role for Lat2 in the supply of thyroid hormone to the cerebral cortex during early postnatal development.
Highlights
Thyroid hormones transport through the cellular plasma membrane is facilitated by several classes of transmembrane proteins
These Mct8-deficient mice display the same alterations of thyroid hormone concentrations as the patients, indicating that the absent or defective function of the Mct8 protein in mice leads to similar alterations of thyroid hormone as those found in patients
The goal of the present work was to evaluate the contribution of Lat2, as a secondary thyroid hormone transporter, to thyroid hormone action in the brain
Summary
Thyroid hormones (thyroxine, T4 and 3,5,39-triiodo-L-thyronine, T3) transport through the cellular plasma membrane is facilitated by several classes of transmembrane proteins. The syndrome is partially replicated in mice with inactivated Mct gene [10,11] These Mct8-deficient mice display the same alterations of thyroid hormone concentrations as the patients, indicating that the absent or defective function of the Mct protein in mice leads to similar alterations of thyroid hormone as those found in patients. These mice present minimal, if any, behavioral deficits of uncertain etiology [12], and do not show the anatomical alterations typical of brain hypothyroidism during postnatal development [12,13]. Enough T3 is still formed locally in the brain to sustain thyroid hormone-dependent gene expression [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
