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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 (RAR\u03b1) signaling as a central molecular network involved in nodule formation. To understand how RAR\u03b1 modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rar\u03b1 knockout mice. Inactivation of Rar\u03b1 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, <jats:italic>Rar\u03b1<\/jats:italic> inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rar\u03b1 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.<\/jats:p>","DOI":"10.1038\/s41598-019-50988-2","type":"journal-article","created":{"date-parts":[[2019,10,11]],"date-time":"2019-10-11T10:04:04Z","timestamp":1570788244000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Retinoic acid receptor \u03b1 as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9757-5614","authenticated-orcid":false,"given":"Rami M.","family":"El Zein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4764-3903","authenticated-orcid":false,"given":"Audrey H.","family":"Soria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Felipe","family":"Golib Dzib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Rickard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio L.","family":"Fernandes-Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Samson-Couterie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Giscos-Douriez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lique","family":"Rocha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marko","family":"Poglitsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso E.","family":"Gomez-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Amar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert B.","family":"Ghyselinck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-823X","authenticated-orcid":false,"given":"Arndt","family":"Benecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria-Christina","family":"Zennaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8796-7534","authenticated-orcid":false,"given":"Sheerazed","family":"Boulkroun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,11]]},"reference":[{"key":"50988_CR1","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1055\/s-0031-1295438","volume":"44","author":"A Hannemann","year":"2012","unstructured":"Hannemann, A. & Wallaschofski, H. 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