title: The Type 3 Deiodinase Is a Critical Determinant of Appropriate Thyroid Hormone Action in the Developing Testis.
abstract: Timely and appropriate levels of thyroid hormone (TH) signaling are necessary to ensure normal developmental outcomes in many tissues. Studies using pharmacological models of altered TH status have revealed an influence of these hormones on testis development and size, but little is known about the role of endogenous determinants of TH action in the developing male gonads. Using a genetic approach, we demonstrate that the type 3 deiodinase (D3), which inactivates TH and protects developing tissues from undue TH action, is a key factor. D3 is highly expressed in the developing testis, and D3-deficient (D3KO) mice exhibit thyrotoxicosis and cell proliferation arrest in the neonatal testis, resulting in an approximately 75% reduction in testis size. This is accompanied by larger seminiferous tubules, impaired spermatogenesis, and a hormonal profile indicative of primary hypogonadism. A deficiency in the TH receptor-α fully normalizes testis size and adult testis gene expression in D3KO mice, indicating that the effects of D3 deficiency are mediated through this type of receptor. Similarly, genetic deficiencies in the D2 or in the monocarboxylate transporter 8 partially rescue the abnormalities in testis size and gonadal axis gene expression featured in the D3KO mice. Our study highlights the testis as an important tissue in which determinants of TH action coordinately converge to ensure normal development and identifies D3 as a critical factor in testis development and in testicular protection from thyrotoxicosis.
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: M Elena
authors.initials: ME
authors.lastname: Martinez
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Aldona
authors.initials: A
authors.lastname: Karaczyn
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: J Patrizia
authors.initials: JP
authors.lastname: Stohn
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: William T
authors.initials: WT
authors.lastname: Donnelly
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Walburga
authors.initials: W
authors.lastname: Croteau
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Galton
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Douglas
authors.initials: D
authors.lastname: Forrest
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Donald
authors.initials: D
authors.lastname: St Germain
authors.affiliation: Department of Molecular Medicine (M.E.M., A.K., J.P.S., D.S.G., A.H.), Maine Medical Center Research Institute, Scarborough, Maine 04074; Departments of Physiology and Neurobiology (W.D., V.A.G.) and Medicine (W.C.), Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756; Rotterdam Thyroid Center (R.P.P.), Department of Internal Medicine, Erasmus MC, 3000 CA Rotterdam, The Netherlands; and Laboratory of Endocrinology and Receptor Biology (R.P.P., D.F.), National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: Arturo
authors.initials: A
authors.lastname: Hernandez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D007006:Hypogonadism / Q000235:genetics*; D007150:Immunohistochemistry; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012671:Seminiferous Tubules / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D013091:Spermatogenesis / Q000235:genetics; D027981:Symporters; D013737:Testis / Q000196:embryology / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics; D013971:Thyrotoxicosis / Q000235:genetics*; D013974:Thyroxine / Q000378:metabolism*; D059467:Transcriptome; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; D027981:Symporters; D037021:Thyroid Hormone Receptors alpha; D013974:Thyroxine; D000097564:Iodothyronine Deiodinase Type II; C484257:Slc16a2 protein, mouse; C117274:iodothyronine deiodinase type III