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Thyroid hormones regulate brain development and function through the control of gene expression, mediated by binding of T 3 to nuclear receptors. Brain T 3 concentration is tightly controlled by homeostatic mechanisms regulating transport and metabolism of T 4 and T 3. We have examined the role of the inactivating enzyme type 3 deiodinase (D3) in the regulation of 43 thyroid hormone-dependent genes in the cerebral cortex of 30-d-old mice. D3 inactivation increased slightly the expression of two of 22 positively regulated genes and significantly decreased the expression of seven of 21 negatively regulated genes. Administration of high doses of T 3 led to significant changes in the expression of 12 positive genes and three negative genes in wild-type mice. The response to T 3 treatment was enhanced in D3-deficient mice, both in the number of genes and in the amplitude of the response, demonstrating the role of D3 in modulating T 3 action. Comparison of the effects on gene expression observed in D3 deficiency with those in hypothyroidism, hyperthyroidism, and type 2 deiodinase (D2) deficiency revealed that the negative genes are more sensitive to D2 and D3 deficiencies than the positive genes. This observation indicates that, in normal physiological conditions, D2 and D3 play critical roles in maintaining local T 3 concentrations within a very narrow range. It also suggests that negatively and positively regulated genes do not have the same physiological significance or that their regulation by thyroid hormone obeys different paradigms at the molecular or cellular levels. Copyright © 2012 by The Endocrine Society. ; This work was supported by Grants SAF2008-01168 and SAF2008-00429-E from the Ministry of Education and Science of Spain, Grant LSHM-CT-2005-018652 from the European Union Integrated ProjectCRESCENDO,a grant from the Center for Biomedical Research on Rare Diseases, an initiative of the Instituto de Salud Carlos III, and by Grant NIMH-083220 from the National Institute of Mental Health. A.C. was recipient of a predoctoral fellowship from the Plan Nacional de I+D+i. ; Peer Reviewed

7 páginas, 4 figuras.-- et al. ; Thyroid hormones influence brain development through the control of gene expression. The concentration of the active hormone T-3 in the brain depends on T-3 transport through the blood-brain barrier, mediated in part by the monocarboxylate transporter 8 (Mct8/MCT8) and the activity of type 2 deiodinase (D2) generating T-3 from T-4. The relative roles of each of these pathways in the regulation of brain gene expression is not known. To shed light on this question, we analyzed thyroid hormone-dependent gene expression in the cerebral cortex of mice with inactivated Mct8 (Slc16a2) and Dio2 genes, alone or in combination. We used 34 target genes identified to be controlled by thyroidhormone in microarray comparisons of cerebral cortex from wild-type control and hypothyroid mice on postnatal d 21. Inactivation of the Mct8 gene (Mct8KO) was without effect on the expression of 31 of these genes. Normal gene expression in the absence of the transporter was mostly due to D2 activity because the combined disruption of Mct8 and Dio2 led to similar effects as hypothyroidism on the expression of 24 genes. Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it increased that of negatively regulated genes. We conclude that gene expression in the Mct8KO cerebral cortex is compensated in part by D2-dependent mechanisms. Intriguingly, positive or negative regulation of genes by thyroid hormone is sensitive to the source of T3 because Dio2 inactivation selectively affects the expression of negatively regulated genes. ; This work was supported by the Center for Biomedical Research on Rare Diseases; Grants SAF2008-01168 and SAF2008-00429E from the Ministry of Science and Innovation, Spain; the European Union Integrated Project CRESCENDO (LSHM-CT-2005-018652) Grants DK15070, DK07011, and DK20595 from the National Institutes of Health; and the Sherman family. A.C. is the holder of a predoctoral fellowship from the Ministry of Science and Innovation of Spain. ; Peer reviewed

Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TR beta-selective GC-24 and the TR beta-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TR beta and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TR alpha or TR beta. This compound, previously shown to be TR alpha-selective in tadpoles, displayed no selectivity in the rat in vivo. ; This work was supported by Ministry of Science of Spain Grants SAF2008-01168 and SAF2008-00429E, the European Union Integrated Project "CRESCENDO", the Center for Biomedical Research on Rare Diseases, the Instituto de Salud Carlos III (J.B.), and the National Institutes of Health Grant DK-52798 (to T.S.S.). ; Peer reviewed

Thyroid hormones are involved in many developmental and physiological processes, including osmoregulation. The regulation of the thyroid system by environmental salinity in the euryhaline gilthead seabream (Sparus aurata) is still poorly characterized. To this end seabreams were exposed to four different environmental salinities (5, 15, 40 and 55 ppt) for 14 days, and plasma free thyroid hormones (fT3, fT4), outer ring deiodination and Na+/K+-ATPase activities in gills and kidney, as well as other osmoregulatory and metabolic parameters were measured. Low salinity conditions (5 ppt) elicited a significant increase in fT3 (29%) and fT4 (184%) plasma concentrations compared to control animals (acclimated to 40 ppt, natural salinity conditions in the Bay of Cádiz, Spain), while the amount of pituitary thyroid stimulating hormone subunit β (tshb) transcript abundance remained unchanged. In addition, plasma fT4 levels were positively correlated to renal and branchial deiodinase type 2 (dio2) mRNA expression. Gill and kidney T4-outer ring deiodination activities correlated positively with dio2 mRNA expression and the highest values were observed in fish acclimated to low salinities (5 and 15 ppt). The high salinity (55 ppt) exposure caused a significant increase in tshb expression (65%), but deiodinase gene expression (dio1 and dio2) and activity did not change and were similar to controls (40 ppt). In conclusion, acclimation to different salinities led to changes in the peripheral regulation of thyroid hormone metabolism in seabream. Therefore, thyroid hormones are involved in the regulation of ion transport and osmoregulatory physiology in this species. The conclusions derived from this study may also allow aquaculturists to modulate thyroid metabolism in seabream by adjusting culture salinity. ; This work was partially supported by a Socrates/Erasmus Grant from the European Union and a Ph.D. scholarship from the University of Cadiz (UCA 2009-074-FPI) to I. R-J. It has been also supported by grants AGL2007-61211/ACU (Ministerio de Educación y Ciencia and FEDER, Spain) and Proyecto de Excelencia PO7-RNM-02843 (Junta de Andalucía) to J.M.M. BL (SFRH/BPD/89889/2012) and PISP (SFRH/BPD/84033/2012) were supported by the Science Foundation (FCT) of Portugal. ; Peer reviewed

Thyroid hormones are involved in many developmental and physiological processes, including osmoregulation. The regulation of the thyroid system by environmental salinity in the euryhaline gilthead seabream (Sparus aurata) is still poorly characterized. To this end seabreams were exposed to four different environmental salinities (5, 15, 40 and 55 ppt) for 14 days, and plasma free thyroid hormones (fT3, ff4), outer ring deiodination and Na+/K+ -ATPase activities in gills and kidney, as well as other osmoregulatory and metabolic parameters were measured. Low salinity conditions (5 ppt) elicited a significant increase in fT3 (29%) and ff4 (184%) plasma concentrations compared to control animals (acclimated to 40 ppt, natural salinity conditions in the Bay of Cadiz, Spain), while the amount of pituitary thyroid stimulating hormone subunit 13 (tshb) transcript abundance remained unchanged. In addition, plasma fT4 levels were positively correlated to renal and branchial deiodinase type 2 (dio2) mRNA expression. Gill and kidney T4-outer ring deiodination activities correlated positively with dio2 mRNA expression and the highest values were observed in fish acclimated to low salinities (5 and 15 ppt). The high salinity (55 ppt) exposure caused a significant increase in tshb expression (65%), but deiodinase gene expression (diol and dio2) and activity did not change and were similar to controls (40 ppt). In conclusion, acclimation to different salinities led to changes in the peripheral regulation of thyroid hormone metabolism in seabream. Therefore, thyroid hormones are involved in the regulation of ion transport and osmoregulatory physiology in this species. The conclusions derived from this study may also allow aquaculturists to modulate thyroid metabolism in seabream by adjusting culture salinity. (C) 2016 Elsevier Inc. All rights reserved. ; Socrates/Erasmus Grant from the European Union ; University of Cadiz [UCA 2009-074-FPI] ; Ministerio de Education y Ciencia, Spain [AGL2007-61211/ACU] ; FEDER, Spain ...

We thank the manuscript reviewers for constructive feedback; David G. Hazlerigg, Cristina Saenz de Miera, and Valerie Simonneaux for genome sequence contributions; Nicolas Scrutton and Lindsey Duguid for expert technical assistance; and Michael Jarsulic for technical assistance on the high-performance computing clusters. This project was supported by a project research grant from The British Society for Neuroendocrinology (to T.J.S.); Grants BB/M021629/1 and BB/M001555/1 (to F.J.P.E.) from the Biotechnology and Biological Sciences Research Council, and Grants UL1-TR000430 (to T.J.S. and B.J.P.) and R01-AI067406 (to B.J.P.) from the National Institutes of Health. T.J.S. is funded by The Leverhulme Trust. The Center for Research Informatics was supported by the Biological Sciences Division at the University of Chicago with additional support provided by the Institute for Translational Medicine/Clinical and Translational award (NIH 5UL1TR002389-02) and the University of Chicago Comprehensive Cancer Center Support Grant (NIH Grant P30CA014599). The bioinformatics analysis was performed on high-performance computing clusters at the Center for Research Informatics, Biological Sciences Division. P.B. was funded by the Scottish Government Rural and Environment Science and Analytical Services Division grant to the Rowett Institute. ; Peer reviewed ; Publisher PDF