Guo Cuicui, Chen Xia, Song Huaidong, Maynard Michelle A, Zhou Yi, Lobanov Alexei V, Gladyshev Vadim N, Ganis Jared J, Wiley David, Jugo Rebecca H, Lee Nicholas Y, Castroneves Luciana A, Zon Leonard I, Scanlan Thomas S, Feldman Henry A, Huang Stephen A
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.
Endocrinology. 2014 Oct;155(10):4069-80. doi: 10.1210/en.2013-2029. Epub 2014 Jul 8.
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.
甲状腺激素是分化和生长的主要调节因子，其作用通过硒酶3型脱碘酶（dio3）催化的内环碘的酶促去除而终止。我们对斑马鱼的研究表明，该物种中dio3基因发生了复制，并且胚胎脱碘是胚胎大小的重要决定因素。尽管两个dio3旁系同源基因都编码对甲状腺激素具有高亲和力的酶活性蛋白，但其解剖学表达模式明显不同，只有在发育中的中枢神经系统中双等位基因表达的硒酶dio3b被敲低的胚胎，在受精后72小时才表现出严重的甲状腺激素依赖性生长受限。这表明，曾经仅被认为是胎盘酶的dio3胚胎缺乏会独立于胎盘生理导致胎儿过小，并增加了人类脱碘胎儿异常可能表现为宫内生长迟缓的有趣可能性。通过绘制所有四种斑马鱼脱碘酶的基因结构和酶学特性，我们还确定dio3b是第一个多外显子dio3基因，其开放阅读框与其硒代半胱氨酸插入序列（SECIS）元件之间有一个大内含子。
