title: Intrinsic expression of a multiexon type 3 deiodinase gene controls zebrafish embryo size.
abstract: Thyroid hormone is a master regulator of differentiation and growth, and its action is terminated by the enzymatic removal of an inner-ring iodine catalyzed by the selenoenzyme type 3 deiodinase (dio3). Our studies of the zebrafish reveal that the dio3 gene is duplicated in this species and that embryonic deiodination is an important determinant of embryo size. Although both dio3 paralogs encode enzymatically active proteins with high affinity for thyroid hormones, their anatomic patterns of expression are markedly divergent and only embryos with knockdown of dio3b, a biallelically expressed selenoenzyme expressed in the developing central nervous system, manifest severe thyroid hormone-dependent growth restriction at 72 hours post fertilization. This indicates that the embryonic deficiency of dio3, once considered only a placental enzyme, causes microsomia independently of placental physiology and raises the intriguing possibility that fetal abnormalities in human deiodination may present as intrauterine growth retardation. By mapping the gene structures and enzymatic properties of all four zebrafish deiodinases, we also identify dio3b as the first multiexon dio3 gene, containing a large intron separating its open reading frame from its selenocysteine insertion sequence (SECIS) element.
authors.affiliation: State Key Laboratory of Medical Genomics (C.G., X.C., H.S.), Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025 China; Thyroid Program of the Division of Endocrinology (C.G., X.C., H.S., M.A.M., R.H.J., N.Y.L., L.A.C., S.A.H.) and Clinical Research Center (H.A.F.), Boston Children's Hospital; Stem Cell Program and Division of Hematology/Oncology (Y.Z., J.J.G., D.W., L.I.Z.), Boston Children's Hospital, Harvard Stem Cell Institute, Harvard Medical School, and Howard Hughes Medical Institute; Department of Medicine (A.V.L., V.N.G., S.A.H.), Brigham and Women's Hospital; Dana Farber Cancer Institute (V.N.G., L.I.Z., S.A.H.), Boston, Massachusetts 02115; and Departments of Physiology and Pharmacology (T.S.S.), Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Guo
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.forename: Huaidong
authors.initials: H
authors.lastname: Song
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Maynard
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Lobanov
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Ganis
authors.forename: David
authors.initials: D
authors.lastname: Wiley
authors.forename: Rebecca H
authors.initials: RH
authors.lastname: Jugo
authors.forename: Nicholas Y
authors.initials: NY
authors.lastname: Lee
authors.forename: Luciana A
authors.initials: LA
authors.lastname: Castroneves
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Zon
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: Henry A
authors.initials: HA
authors.lastname: Feldman
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Huang
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D049628:Body Size / Q000235:genetics*; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D007527:Isoenzymes / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics*
chemical_list: D007527:Isoenzymes; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase