title: MCT8 Deficiency in Male Mice Mitigates the Phenotypic Abnormalities Associated With the Absence of a Functional Type 3 Deiodinase.
abstract: Mice deficient in the type 3 deiodinase (D3KO mice) manifest impaired clearance of thyroid hormone (TH), leading to elevated levels of TH action during development. This alteration causes reduced neonatal viability, growth retardation, and central hypothyroidism. Here we examined how these phenotypes are affected by a deficiency in the monocarboxylate transporter 8 (MCT8), which is a major contributor to the transport of the active thyroid hormone, T3, into the cell. MCT8 deficiency eliminated the neonatal lethality of type 3 deiodinase (D3)-deficient mice and significantly ameliorated their growth retardation. Double-mutant newborn mice exhibited similar peripheral thyrotoxicosis and increased brain expression of T3-dependent genes as mice with D3 deficiency only. Later in neonatal life and adulthood, double-mutant mice manifested central and peripheral TH status similar to mice with single MCT8 deficiency, with low serum T4, elevated serum TSH and T3, and decreased T3-dependent gene expression in the hypothalamus. In double-mutant adult mice, both thyroid gland size and the hypothyroidism-induced rise in TSH were greater than those in mice with single D3 deficiency but less than those in mice with MCT8 deficiency alone. Our results demonstrate that the marked phenotypic abnormalities observed in the D3-deficient mouse, including perinatal mortality, growth retardation, and central hypothyroidism in adult animals, require expression of MCT8, confirming the interdependent relationship between the TH transport into cells and the deiodination processes.
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: J Patrizia
authors.initials: JP
authors.lastname: Stohn
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: M Elena
authors.initials: ME
authors.lastname: Martinez
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Kassey
authors.initials: K
authors.lastname: Matoin
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Morte
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Juan
authors.initials: J
authors.lastname: Bernal
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Valerie Anne
authors.initials: VA
authors.lastname: Galton
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Donald
authors.initials: D
authors.lastname: St Germain
authors.affiliation: Center of Molecular Medicine (J.P.S., M.E.M., K.M., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Instituto de Investigaciones Biomedicas (B.M., J.B.), Consejo Superior de Investigaciones Científicas and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain; and Department of Physiology and Neurobiology (V.A.G.), Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire 03756.
authors.forename: Arturo
authors.initials: A
authors.lastname: Hernandez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005317:Fetal Growth Retardation / Q000235:genetics; D005328:Fetal Viability / Q000235:genetics; D048788:Growth and Development / Q000235:genetics; D007031:Hypothalamus / Q000502:physiology; D007037:Hypothyroidism / Q000235:genetics; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D010641:Phenotype; D027981:Symporters; D013961:Thyroid Gland / Q000502:physiology
chemical_list: D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C484257:Slc16a2 protein, mouse; D027981:Symporters; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase