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The expression of the Y-linked gene <jats:italic>SRY<\/jats:italic> is sufficient to trigger the testicular pathway, whereas its absence in XX embryos leads to ovarian differentiation. Yet, the potential involvement of non-coding regulation in this process remains unclear. Here we show that the deletion of a single microRNA cluster, <jats:italic>miR-17<\/jats:italic>~<jats:italic>92<\/jats:italic>, induces complete primary male-to-female sex reversal in XY mice. <jats:italic>Sry<\/jats:italic> expression is delayed in XY knockout gonads, which develop as ovaries. Sertoli cell differentiation is reduced, delayed and unable to sustain testicular development. Pre-supporting cells in mutant gonads undergo a transient state of sex ambiguity which is subsequently resolved towards the ovarian fate. The <jats:italic>miR-17<\/jats:italic>~<jats:italic>92<\/jats:italic> predicted target genes are upregulated, affecting the fine regulation of gene networks controlling gonad development. Thus, microRNAs emerge as key components for mammalian sex determination, controlling <jats:italic>Sry<\/jats:italic> expression timing and Sertoli cell differentiation.<\/jats:p>","DOI":"10.1038\/s41467-024-47658-x","type":"journal-article","created":{"date-parts":[[2024,5,7]],"date-time":"2024-05-07T13:02:25Z","timestamp":1715086945000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6267-704X","authenticated-orcid":false,"given":"Alicia","family":"Hurtado","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8308-8017","authenticated-orcid":false,"given":"Irene","family":"Mota-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6707-6825","authenticated-orcid":false,"given":"Miguel","family":"Lao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0692-2260","authenticated-orcid":false,"given":"Francisca M.","family":"Real","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Jedamzick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4446-9313","authenticated-orcid":false,"given":"Miguel","family":"Burgos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3165-036X","authenticated-orcid":false,"given":"Dar\u00edo G.","family":"Lupi\u00e1\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4103-8219","authenticated-orcid":false,"given":"Rafael","family":"Jim\u00e9nez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2651-1530","authenticated-orcid":false,"given":"Francisco J.","family":"Barrionuevo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,7]]},"reference":[{"key":"47658_CR1","doi-asserted-by":"crossref","unstructured":"Nef, S., St\u00e9vant, I. & Greenfield, A. 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