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Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only

BACKGROUND: In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial. METHODS: The TRα(AMI) knock-in allele allows the generation of transgenic mi...

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Autores principales: Fumel, Betty, Froment, Pascal, Holzenberger, Martin, Livera, Gabriel, Monget, Philippe, Fouchécourt, Sophie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368620/
https://www.ncbi.nlm.nih.gov/pubmed/25793522
http://dx.doi.org/10.1371/journal.pone.0119392
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author Fumel, Betty
Froment, Pascal
Holzenberger, Martin
Livera, Gabriel
Monget, Philippe
Fouchécourt, Sophie
author_facet Fumel, Betty
Froment, Pascal
Holzenberger, Martin
Livera, Gabriel
Monget, Philippe
Fouchécourt, Sophie
author_sort Fumel, Betty
collection PubMed
description BACKGROUND: In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial. METHODS: The TRα(AMI) knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRα1 (thyroid receptor α1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO-iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter. FINDINGS: We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRα(AMI) specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRα(AMI)-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRα(AMI)-ARO males showed normal fertility. This phenotype is similar to TRα(AMI)-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRα(AMI)-ARO. CONCLUSIONS/SIGNIFICANCE: We concluded that the presence of a mutant TRα(AMI) allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRα1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis.
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spelling pubmed-43686202015-03-27 Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only Fumel, Betty Froment, Pascal Holzenberger, Martin Livera, Gabriel Monget, Philippe Fouchécourt, Sophie PLoS One Research Article BACKGROUND: In the testis, thyroid hormone (T3) regulates the number of gametes produced through its action on Sertoli cell proliferation. However, the role of T3 in the regulation of steroidogenesis is still controversial. METHODS: The TRα(AMI) knock-in allele allows the generation of transgenic mice expressing a dominant-negative TRα1 (thyroid receptor α1) isoform restricted to specific target cells after Cre-loxP recombination. Here, we introduced this mutant allele in both Sertoli and Leydig cells using a novel aromatase-iCre (ARO-iCre) line that expresses Cre recombinase under control of the human Cyp19(IIa)/aromatase promoter. FINDINGS: We showed that loxP recombination induced by this ARO-iCre is restricted to male and female gonads, and is effective in Sertoli and Leydig cells, but not in germ cells. We compared this model with the previous introduction of TRα(AMI) specifically in Sertoli cells in order to investigate T3 regulation of steroidogenesis. We demonstrated that TRα(AMI)-ARO males exhibited increased testis weight, increased sperm reserve in adulthood correlated to an increased proliferative index at P3 in vivo, and a loss of T3-response in vitro. Nevertheless, TRα(AMI)-ARO males showed normal fertility. This phenotype is similar to TRα(AMI)-SC males. Importantly, plasma testosterone and luteinizing hormone levels, as well as mRNA levels of steroidogenesis enzymes StAR, Cyp11a1 and Cyp17a1 were not affected in TRα(AMI)-ARO. CONCLUSIONS/SIGNIFICANCE: We concluded that the presence of a mutant TRα(AMI) allele in both Leydig and Sertoli cells does not accentuate the phenotype in comparison with its presence in Sertoli cells only. This suggests that direct T3 regulation of steroidogenesis through TRα1 is moderate in Leydig cells, and that Sertoli cells are the main target of T3 action in the testis. Public Library of Science 2015-03-20 /pmc/articles/PMC4368620/ /pubmed/25793522 http://dx.doi.org/10.1371/journal.pone.0119392 Text en © 2015 Fumel et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Fumel, Betty
Froment, Pascal
Holzenberger, Martin
Livera, Gabriel
Monget, Philippe
Fouchécourt, Sophie
Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only
title Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only
title_full Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only
title_fullStr Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only
title_full_unstemmed Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only
title_short Expression of Dominant-Negative Thyroid Hormone Receptor Alpha1 in Leydig and Sertoli Cells Demonstrates No Additional Defect Compared with Expression in Sertoli Cells Only
title_sort expression of dominant-negative thyroid hormone receptor alpha1 in leydig and sertoli cells demonstrates no additional defect compared with expression in sertoli cells only
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368620/
https://www.ncbi.nlm.nih.gov/pubmed/25793522
http://dx.doi.org/10.1371/journal.pone.0119392
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