Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster Hurtado, Alicia Mota Gómez, Irene Lao Pérez, Miguel Real, Francisca M. Jedamzick, Johanna Burgos Poyatos, Miguel G. Lupiáñez, Darío Jiménez Medina, Rafael Barrionuevo, Francisco J. 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. 2024-07-24T08:49:10Z 2024-07-24T08:49:10Z 2024-05-07 journal article Hurtado, A. et. al. Nat Commun 15, 3809 (2024). [https://doi.org/10.1038/s41467-024-47658-x] https://hdl.handle.net/10481/93437 10.1038/s41467-024-47658-x eng info:eu-repo/grantAgreement/ERC/H2020/101045439 http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Nature communications