title: The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signaling network.
abstract: During early development of female mouse embryos, both X chromosomes are transiently active. X gene dosage is then equalized between the sexes through the process of X chromosome inactivation (XCI). Whether the double dose of X-linked genes in females compared with males leads to sex-specific developmental differences has remained unclear. Using embryonic stem cells with distinct sex chromosome compositions as a model system, we show that two X chromosomes stabilize the naive pluripotent state by inhibiting MAPK and Gsk3 signaling and stimulating the Akt pathway. Since MAPK signaling is required to exit the pluripotent state, differentiation is paused in female cells as long as both X chromosomes are active. By preventing XCI or triggering it precociously, we demonstrate that this differentiation block is released once XX cells have undergone X inactivation. We propose that double X dosage interferes with differentiation, thus ensuring a tight coupling between X chromosome dosage compensation and development.
authors: Mammalian Developmental Epigenetics Group, Institut Curie, CNRS UMR 3215, INSERM U934, Paris 75248, France. Electronic address: edda.schulz@curie.fr.
authors: Edda G
authors: EG
authors: Schulz
authors: Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany; Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany.
authors: Johannes
authors: J
authors: Meisig
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Tomonori
authors: T
authors: Nakamura
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Ikuhiro
authors: I
authors: Okamoto
authors: Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany; Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany.
authors: Anja
authors: A
authors: Sieber
authors: Mammalian Developmental Epigenetics Group, Institut Curie, CNRS UMR 3215, INSERM U934, Paris 75248, France.
authors: Christel
authors: C
authors: Picard
authors: Mammalian Developmental Epigenetics Group, Institut Curie, CNRS UMR 3215, INSERM U934, Paris 75248, France.
authors: Maud
authors: M
authors: Borensztein
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Mitinori
authors: M
authors: Saitou
authors: Institute of Pathology, Charité-Universitätsmedizin, 10117 Berlin, Germany; Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt Universität, 10115 Berlin, Germany.
authors: Nils
authors: N
authors: Blüthgen
authors: Mammalian Developmental Epigenetics Group, Institut Curie, CNRS UMR 3215, INSERM U934, Paris 75248, France. Electronic address: edith.heard@curie.fr.
authors: Edith
authors: E
authors: Heard
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D004303:Dosage Compensation, Genetic; D053595:Embryonic Stem Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014960:X Chromosome / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D020928:Mitogen-Activated Protein Kinases; D062085:RNA, Long Noncoding; D000097584:DNA Methyltransferase 3B; C077885:XIST non-coding RNA