title: Calcineurin-NFAT signaling critically regulates early lineage specification in mouse embryonic stem cells and embryos.
abstract: Self-renewal and pluripotency are hallmarks of embryonic stem cells (ESCs). However, the signaling pathways that trigger their transition from self-renewal to differentiation remain elusive. Here, we report that calcineurin-NFAT signaling is both necessary and sufficient to switch ESCs from an undifferentiated state to lineage-specific cells and that the inhibition of this pathway can maintain long-term ESC self-renewal independent of leukemia inhibitory factor. Mechanistically, this pathway converges with the Erk1/2 pathway to regulate Src expression and promote the epithelial-mesenchymal transition (EMT), a process required for lineage specification in response to differentiation stimuli. Furthermore, calcineurin-NFAT signaling is activated when the earliest differentiation event occurs in mouse embryos, and its inhibition disrupts extraembryonic lineage development. Collectively, our results demonstrate that the NFAT and Erk1/2 cascades form a signaling switch for early lineage segregation in mouse ESCs and provide significant insights into the regulation of the balance between ESC self-renewal and early lineage specification.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.forename: Acong
authors.initials: A
authors.lastname: Yang
authors.forename: Jiangwei
authors.initials: J
authors.lastname: Lin
authors.forename: Fan
authors.initials: F
authors.lastname: Tang
authors.forename: Shibo
authors.initials: S
authors.lastname: Jin
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wei
authors.forename: Jinsong
authors.initials: J
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D050778:NFATC Transcription Factors; D019703:Calcineurin