title: A genetic and developmental pathway from STAT3 to the OCT4-NANOG circuit is essential for maintenance of ICM lineages in vivo.
abstract: Although it is known that OCT4-NANOG are required for maintenance of pluripotent cells in vitro, the upstream signals that regulate this circuit during early development in vivo have not been identified. Here we demonstrate, for the first time, signal transducers and activators of transcription 3 (STAT3)-dependent regulation of the OCT4-NANOG circuitry necessary to maintain the pluripotent inner cell mass (ICM), the source of in vitro-derived embryonic stem cells (ESCs). We show that STAT3 is highly expressed in mouse oocytes and becomes phosphorylated and translocates to the nucleus in the four-cell and later stage embryos. Using leukemia inhibitory factor (Lif)-null embryos, we found that STAT3 phosphorylation is dependent on LIF in four-cell stage embryos. In blastocysts, interleukin 6 (IL-6) acts in an autocrine fashion to ensure STAT3 phosphorylation, mediated by janus kinase 1 (JAK1), a LIF- and IL-6-dependent kinase. Using genetically engineered mouse strains to eliminate Stat3 in oocytes and embryos, we firmly establish that STAT3 is essential for maintenance of ICM lineages but not for ICM and trophectoderm formation. Indeed, STAT3 directly binds to the Oct4 and Nanog distal enhancers, modulating their expression to maintain pluripotency of mouse embryonic and induced pluripotent stem cells. These results provide a novel genetic model of cell fate determination operating through STAT3 in the preimplantation embryo and pluripotent stem cells in vivo.
authors.affiliation: Cancer Science Institute of Singapore, Singapore 117599, Singapore.
authors.forename: Dang Vinh
authors.initials: DV
authors.lastname: Do
authors.forename: Jun
authors.initials: J
authors.lastname: Ueda
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Messerschmidt
authors.forename: Chanchao
authors.initials: C
authors.lastname: Lorthongpanich
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Guoji
authors.initials: G
authors.lastname: Guo
authors.forename: Peiyu J
authors.initials: PJ
authors.lastname: Lin
authors.forename: Md Zakir
authors.initials: MZ
authors.lastname: Hossain
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.forename: Akira
authors.initials: A
authors.lastname: Moh
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wu
authors.forename: Paul
authors.initials: P
authors.lastname: Robson
authors.forename: Huck Hui
authors.initials: HH
authors.lastname: Ng
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Knowles
authors.forename: Davor
authors.initials: D
authors.lastname: Solter
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Fu
mesh_terms: D000818:Animals; D053624:Blastocyst Inner Cell Mass / Q000166:cytology / Q000378:metabolism; D019070:Cell Lineage; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000502:physiology; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1
keywords: NANOG; OCT4; STAT3; embryogenesis; embryonic stem cell; inner cell mass