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Sodium/Iodide Symporter (NIS) Gene Expression Is the Limiting Step for the Onset of Thyroid Function in the Human Fetus

Faculty of Medicine René Descartes (G.S., A.C., M.P.), Paris V, Site Necker, Institut National de la Santé et de la Recherche Médicale Equipe Mixte 0363, and Pediatric Endocrine Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, 75743 Paris, France; Department of Clinical Biology (L.L., J.-M.B.), Institut Gustave-Roussy, 94805 Villejuif, France; Faculty of Medicine Denis Diderot (F.G., A.-L.D.), Paris VII, and Department of Developmental Biology, AP-HP, Hôpital Robert Debré, 75019 Paris, France; Department of Pathology (M.T., B.C.), Institut Gustave-Roussy, 94805 Villejuif, France; Department of Cytogenetics (J.M., M.V.), Hôpital Necker Enfants-Malades, 75743 Paris, France; Biostatistics and Epidemiology Unit (S.M.), Institut Gustave-Roussy, 94805 Villejuif, France; and Department of Nuclear Medicine (M.S.), Institut Gustave-Roussy, 94805 Villejuif, France

Address all correspondence and requests for reprints to: Professor Michel Polak, M.D., Ph.D., Service d’Endocrinologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades and Faculté de Médecine René Descartes, Paris V, Institut National de la Santé et de la Recherche Médicale Equipe Mixte 0363, 149, rue de Sèvres, F-75743 Paris, Cedex 15, France. E-mail: michel.polak{at}nck.aphp.fr.

Context: Terminal differentiation of the human thyroid is characterized by the onset of follicle formation and thyroid hormone synthesis at 11 gestational weeks (GW).

Objective: This study aimed to investigate the ontogeny of thyroglobulin (Tg), thyroid peroxidase (TPO), sodium/iodide symporter (NIS), pendrin (PDS), dual oxidase 2 (DUOX2), thyroid-stimulating hormone receptor (TSHR), and thyroid transcription factor 1 (TITF1), forkhead box E1 (FOXE1), and paired box gene 8 (PAX8) in the developing human thyroid.

Design: Thyroid tissues from human embryos and fetuses (7–33 GW; n = 45) were analyzed by quantitative PCR to monitor mRNA expression for each gene and by immunohistochemistry to determine the cellular distribution of TITF1, TSHR, Tg, TPO, NIS, and the onset of T₄ production. A broken line regression model was fitted for each gene to compare the loglinear increase in expression before and after the onset of T₄ synthesis.

Results: TITF1, FOXE1, PAX8, TSHR, and DUOX2 were stably expressed from 7 to 33 GW. Tg, TPO, and PDS expression was detectable as early as 7 GW and was correlated with gestational age (all, P < 0.01), and the slope of the regression line was significantly different before and after the onset of T₄ synthesis at 11 GW (all, P < 0.01). NIS expression appeared last and showed the highest fit by the broken line regression model of all genes (correlation age P < 0.0001, broken line regression P < 0.0001). Immunohistochemical studies detected TITF1, TSHR, and Tg in unpolarized thyrocytes before follicle formation. T₄ and NIS labeling were only found in developing follicles from 11 GW on.

Conclusion: These results imply a key role of NIS for the onset of human thyroid function.

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