Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster

• Published in: Nature communications 2024-05, Vol.15 (1), p.3809-3809, Article 3809
• Main Authors: Hurtado, Alicia, Mota-Gómez, Irene, Lao, Miguel, Real, Francisca M., Jedamzick, Johanna, Burgos, Miguel, Lupiáñez, Darío G., Jiménez, Rafael, Barrionuevo, Francisco J.
• Format: Article
• Language: English
• Subjects: 38; 38/1; 38/23; 38/39; 38/70; 38/77; 38/91; 631/136/2128; 631/208/135; 64; 64/60; Animals; Cell differentiation; Cell Differentiation - genetics; Clusters; Differentiation (biology); Disorders of Sex Development - genetics; Embryos; Female; Females; Gene expression; Gene Expression Regulation, Developmental; Genes; Gonads; Gonads - metabolism; Humanities and Social Sciences; Male; Males; Mammals; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Ovaries; Ovary - metabolism; Science; Science (multidisciplinary); Sertoli Cells - cytology; Sertoli Cells - metabolism; Sex; Sex determination; Sex Determination Processes - genetics; Sex Differentiation - genetics; Sex reversal; Sex-Determining Region Y Protein - genetics; Sex-Determining Region Y Protein - metabolism; Signal transduction; Testes; Testis - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47658-x

Mammalian sex determination is controlled by antagonistic gene cascades operating in embryonic undifferentiated gonads. The expression of the Y-linked gene SRY 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, miR-17 ~ 92 , induces complete primary male-to-female sex reversal in XY mice. Sry 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 miR-17 ~ 92 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 Sry expression timing and Sertoli cell differentiation. The cluster miR-17 ~ 92 modulates the expression of genes networks and signalling pathways to ensure proper Sry expression timing and subsequent testis differentiation, an unexpected role for miRNAs in the early steps of mammalian sex determination.