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

Alicia Hurtado, Irene Mota-Gómez, Miguel Lao, Francisca M. Real, Johanna Jedamzick, Miguel Burgos, Darío G. Lupiáñez (), Rafael Jiménez () and Francisco J. Barrionuevo ()
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Alicia Hurtado: Labs. 127 and A105, Centre for Biomedical Research, University of Granada, Armilla
Irene Mota-Gómez: Max-Delbrück Center for Molecular Medicine
Miguel Lao: Labs. 127 and A105, Centre for Biomedical Research, University of Granada, Armilla
Francisca M. Real: Max Planck Institute for Molecular Genetics
Johanna Jedamzick: Max-Delbrück Center for Molecular Medicine
Miguel Burgos: Labs. 127 and A105, Centre for Biomedical Research, University of Granada, Armilla
Darío G. Lupiáñez: Max-Delbrück Center for Molecular Medicine
Rafael Jiménez: Labs. 127 and A105, Centre for Biomedical Research, University of Granada, Armilla
Francisco J. Barrionuevo: Labs. 127 and A105, Centre for Biomedical Research, University of Granada, Armilla

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-47658-x

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