Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling

Abstract Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We perfo...

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Autores principales:	Rami M. El Zein, Audrey H. Soria, Jose Felipe Golib Dzib, Amanda J. Rickard, Fabio L. Fernandes-Rosa, Benoit Samson-Couterie, Isabelle Giscos-Douriez, Angélique Rocha, Marko Poglitsch, Celso E. Gomez-Sanchez, Laurence Amar, Norbert B. Ghyselinck, Arndt Benecke, Maria-Christina Zennaro, Sheerazed Boulkroun
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3cff1a93869f4413b2da69cfd919de81
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spelling	oai:doaj.org-article:3cff1a93869f4413b2da69cfd919de812021-12-02T15:08:31ZRetinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling10.1038/s41598-019-50988-22045-2322https://doaj.org/article/3cff1a93869f4413b2da69cfd919de812019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-50988-2https://doaj.org/toc/2045-2322Abstract Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.Rami M. El ZeinAudrey H. SoriaJose Felipe Golib DzibAmanda J. RickardFabio L. Fernandes-RosaBenoit Samson-CouterieIsabelle Giscos-DouriezAngélique RochaMarko PoglitschCelso E. Gomez-SanchezLaurence AmarNorbert B. GhyselinckArndt BeneckeMaria-Christina ZennaroSheerazed BoulkrounNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-20 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rami M. El Zein Audrey H. Soria Jose Felipe Golib Dzib Amanda J. Rickard Fabio L. Fernandes-Rosa Benoit Samson-Couterie Isabelle Giscos-Douriez Angélique Rocha Marko Poglitsch Celso E. Gomez-Sanchez Laurence Amar Norbert B. Ghyselinck Arndt Benecke Maria-Christina Zennaro Sheerazed Boulkroun Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling
description	Abstract Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. Inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA.
format	article
author	Rami M. El Zein Audrey H. Soria Jose Felipe Golib Dzib Amanda J. Rickard Fabio L. Fernandes-Rosa Benoit Samson-Couterie Isabelle Giscos-Douriez Angélique Rocha Marko Poglitsch Celso E. Gomez-Sanchez Laurence Amar Norbert B. Ghyselinck Arndt Benecke Maria-Christina Zennaro Sheerazed Boulkroun
author_facet	Rami M. El Zein Audrey H. Soria Jose Felipe Golib Dzib Amanda J. Rickard Fabio L. Fernandes-Rosa Benoit Samson-Couterie Isabelle Giscos-Douriez Angélique Rocha Marko Poglitsch Celso E. Gomez-Sanchez Laurence Amar Norbert B. Ghyselinck Arndt Benecke Maria-Christina Zennaro Sheerazed Boulkroun
author_sort	Rami M. El Zein
title	Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling
title_short	Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling
title_full	Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling
title_fullStr	Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling
title_full_unstemmed	Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling
title_sort	retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with wnt and vegfa signalling
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/3cff1a93869f4413b2da69cfd919de81
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Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling

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