title: Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8.
abstract: The monocarboxylate transporter 8 (MCT8) plays a critical role in mediating the uptake of thyroid hormones (THs) into the brain. In patients, inactivating mutations in the MCT8 gene are associated with a severe form of psychomotor retardation and abnormal serum TH levels. Here, we evaluate the therapeutic potential of the TH analog 3,5,3',5'-tetraiodothyroacetic acid (tetrac) as a replacement for T(4) in brain development. Using COS1 cells transfected with TH transporter and deiodinase constructs, we could show that tetrac, albeit not being transported by MCT8, can be metabolized to the TH receptor active compound 3,3',5-triiodothyroacetic acid (triac) by type 2 deiodinase and inactivated by type 3 deiodinase. Triac in turn is capable of replacing T(3) in primary murine cerebellar cultures where it potently stimulates Purkinje cell development. In vivo effects of tetrac were assessed in congenital hypothyroid Pax8-knockout (KO) and Mct8/Pax8 double-KO mice as well as in Mct8-KO and wild-type animals after daily injection of tetrac (400 ng/g body weight) during the first postnatal weeks. This treatment was sufficient to promote TH-dependent neuronal differentiation in the cerebellum, cerebral cortex, and striatum but was ineffective in suppressing hypothalamic TRH expression. In contrast, TSH transcript levels in the pituitary were strongly down-regulated in response to tetrac. Based on our findings we propose that tetrac administration offers the opportunity to provide neurons during the postnatal stage with a potent TH receptor agonist, thereby eventually reducing the neurological damage in patients with MCT8 mutations without deteriorating the thyrotoxic situation in peripheral tissues.
authors: Leibniz Institute for Age Research/Fritz Lipmann Institute, D-07745 Jena, Germany.
authors: Sigrun
authors: S
authors: Horn
authors: Simone
authors: S
authors: Kersseboom
authors: Steffen
authors: S
authors: Mayerl
authors: Julia
authors: J
authors: Müller
authors: Claudia
authors: C
authors: Groba
authors: Marija
authors: M
authors: Trajkovic-Arsic
authors: Tobias
authors: T
authors: Ackermann
authors: Theo J
authors: TJ
authors: Visser
authors: Heike
authors: H
authors: Heuer
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development; D019556:COS Cells; D002522:Chlorocebus aethiops; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D013974:Thyroxine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C484257:Slc16a2 protein, mouse; D027981:Symporters; C011126:tetraiodothyroacetic acid; D013974:Thyroxine