title: Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst.
abstract: The transcription factor Oct4 is required in vitro for establishment and maintenance of embryonic stem cells and for reprogramming somatic cells to pluripotency. In vivo, it prevents the ectopic differentiation of early embryos into trophoblast. Here, we further explore the role of Oct4 in blastocyst formation and specification of epiblast versus primitive endoderm lineages using conditional genetic deletion. Experiments involving mouse embryos deficient for both maternal and zygotic Oct4 suggest that it is dispensable for zygote formation, early cleavage and activation of Nanog expression. Nanog protein is significantly elevated in the presumptive inner cell mass of Oct4 null embryos, suggesting an unexpected role for Oct4 in attenuating the level of Nanog, which might be significant for priming differentiation during epiblast maturation. Induced deletion of Oct4 during the morula to blastocyst transition disrupts the ability of inner cell mass cells to adopt lineage-specific identity and acquire the molecular profile characteristic of either epiblast or primitive endoderm. Sox17, a marker of primitive endoderm, is not detected following prolonged culture of such embryos, but can be rescued by provision of exogenous FGF4. Interestingly, functional primitive endoderm can be rescued in Oct4-deficient embryos in embryonic stem cell complementation assays, but only if the host embryos are at the pre-blastocyst stage. We conclude that cell fate decisions within the inner cell mass are dependent upon Oct4 and that Oct4 is not cell-autonomously required for the differentiation of primitive endoderm derivatives, as long as an appropriate developmental environment is established.
authors: Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors: Gloryn Chia
authors: GC
authors: Le Bin
authors: Silvia
authors: S
authors: Muñoz-Descalzo
authors: Agata
authors: A
authors: Kurowski
authors: Harry
authors: H
authors: Leitch
authors: Xinghua
authors: X
authors: Lou
authors: William
authors: W
authors: Mansfield
authors: Charles
authors: C
authors: Etienne-Dumeau
authors: Nils
authors: N
authors: Grabole
authors: Carla
authors: C
authors: Mulas
authors: Hitoshi
authors: H
authors: Niwa
authors: Anna-Katerina
authors: AK
authors: Hadjantonakis
authors: Jennifer
authors: J
authors: Nichols
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009028:Morula / Q000166:cytology / Q000378:metabolism; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism; D015053:Zygote / Q000166:cytology / Q000378:metabolism
chemical_list: D024002:HMGB Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D050814:Octamer Transcription Factor-3; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse
keywords: Blastocyst; Chimaera; Nanog; Oct4 (Pou5f1); Primitive endoderm; Sox17