title: PRC1 coordinates timing of sexual differentiation of female primordial germ cells.
abstract: In mammals, sex differentiation of primordial germ cells (PGCs) is determined by extrinsic cues from the environment. 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 mesonephroi. Given the widespread role of retinoic acid signalling during development, the molecular mechanisms that enable PGCs to express Stra8 and enter meiosis in a timely manner are unknown. Here we identify gene-dosage-dependent roles in PGC development for Ring1 and Rnf2, two central components of the Polycomb repressive complex 1 (PRC1). 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 expression, 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.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
authors.forename: Shihori
authors.initials: S
authors.lastname: Yokobayashi
authors.forename: Ching-Yeu
authors.initials: CY
authors.lastname: Liang
authors.forename: Hubertus
authors.initials: H
authors.lastname: Kohler
authors.forename: Peter
authors.initials: P
authors.lastname: Nestorov
authors.forename: Zichuan
authors.initials: Z
authors.lastname: Liu
authors.forename: Miguel
authors.initials: M
authors.lastname: Vidal
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
authors.forename: Tim C
authors.initials: TC
authors.lastname: Roloff
authors.forename: Antoine H F M
authors.initials: AH
authors.lastname: Peters
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D008297:Male; D008540:Meiosis; D051379:Mice; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010063:Ovum / Q000166:cytology* / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000172:deficiency / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000502:physiology*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D011506:Proteins; C102019:Stra8 protein, mouse; D014212:Tretinoin; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; C489840:Ring1 protein, mouse; C489842:Rnf2 protein, mouse; D044767:Ubiquitin-Protein Ligases