In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment1. In mouse female PGCs, expression of stimulated by retinoic acid gene 8 (Stra8) and meiosis are induced in response to retinoic acid provided from the mesonephroi2,3,4,5. Given the widespread role of retinoic acid signalling during development6,7, the molecular mechanisms that enable PGCs to express Stra8 and enter meiosis in a timely manner are unknown2,8. Here we identify gene-dosage-dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb repressive complex 1 (PRC1)9,10. Both paralogues are essential for PGC development between days 10.5 and 11.5 of gestation. Rnf2 is subsequently required in female PGCs to maintain high levels of Oct4 (also known as Pou5f1) and Nanog expression11, and to prevent premature induction of meiotic gene expression and entry into meiotic prophase. Chemical inhibition of retinoic acid signalling partially suppresses precocious Oct4 downregulation and Stra8 activation in Rnf2-deficient female PGCs. Chromatin immunoprecipitation analyses show that Stra8 is a direct target of PRC1 and PRC2 in PGCs. These data demonstrate the importance of PRC1 gene dosage in PGC development and in coordinating the timing of sex differentiation of female PGCs by antagonizing extrinsic retinoic acid signalling.
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We thank A. Nagy and H. Schöler for the Tnap-cre and Oct4(ΔPE)–GFP mice, respectively, and M. Griswold for the Stra8 antibody. We are grateful to L. Gelman (microscopy and imaging), L. Burger, M. Stadler (bioinformatics), E. Cabuy, S. Thiry, K. Jacobeit (functional genomics) and the FMI animal facility for assistance. We thank members of the Peters laboratory, particularly M. Tardat, S. Erkek and M. Gill, for experimental support and discussions. S.Y. is a recipient of a Human Frontier Science Program long-term fellowship and a Japan Society for the Promotion of Science postdoctoral fellowship. Research in the Peters laboratory is supported by the Novartis Research Foundation, the Swiss National Science Foundation (31003A_125386 and NRP 63 - Stem Cells and Regenerative Medicine), SystemsX.ch (Cell plasticity), the Japanese Swiss Science and Technology Cooperation Program, the European Network of Excellence ‘The Epigenome’ and the EMBO Young Investigator program.
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-11, full legends for Supplementary Tables 1 and 2 and Supplementary References. (PDF 5198 kb)
This file contains Supplementary Table 1, which shows lists of genes that are differentially expressed in Rnf2Δ and Ring1Δ/Rnf2Δ PGCs versus control PGCs as well as during development of normal PGCs according to microarray and RNA-sequencing analyses – see Supplementary Information pdf for full legend. (XLSX 362 kb)
This file contains Supplementary Table 2, which shows a list of GO terms that are over-represented in groups of genes mis-regulated in Rnf2Δ and Ring1Δ/Rnf2Δ PGCs. (XLSX 64 kb)
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Yokobayashi, S., Liang, CY., Kohler, H. et al. PRC1 coordinates timing of sexual differentiation of female primordial germ cells. Nature 495, 236–240 (2013). https://doi.org/10.1038/nature11918
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