title: Cerebral cortex hyperthyroidism of newborn mct8-deficient mice transiently suppressed by lat2 inactivation.
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.
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Núñez
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Martínez de Mena
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain.
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Obregon
authors.affiliation: Laboratorio de Genètica Molecular, IDIBELL, Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER) Unit 730, Barcelona, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Font-Llitjós
authors.affiliation: Laboratorio de Genètica Molecular, IDIBELL, Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER) Unit 730, Barcelona, Spain; Sección de Genética, Departamento de Ciencias Fisiológicas II, Facultad de Medicina, Universidad de Barcelona, Barcelona, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Nunes
authors.affiliation: Institute for Research in Biomedicine (IRB), Barcelona, Spain; CIBERER Unit 731, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Dumitrescu
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain; CIBERER Unit 708, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morte
authors.affiliation: Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC) and Universidad Autónoma de Madrid (UAM), Madrid, Spain; CIBERER Unit 708, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Bernal
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000378:metabolism*; D005260:Female; D027301:Fusion Regulatory Protein 1, Light Chains / Q000235:genetics / Q000378:metabolism*; D006980:Hyperthyroidism / Q000235:genetics / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D027182:Amino Acid Transport System y+; D027301:Fusion Regulatory Protein 1, Light Chains; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C518286:SLC7A8 protein, mouse; C484257:Slc16a2 protein, mouse; D027981:Symporters; D014284:Triiodothyronine