{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:24:55Z","timestamp":1791275095155,"version":"4.1.0"},"reference-count":41,"publisher":"The Company of Biologists","issue":"5","license":[{"start":{"date-parts":[[2020,9,5]],"date-time":"2020-09-05T00:00:00Z","timestamp":1599264000000},"content-version":"vor","delay-in-days":2380,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,3,1]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1242\/dev.096875","type":"journal-article","created":{"date-parts":[[2014,2,7]],"date-time":"2014-02-07T00:10:52Z","timestamp":1391731852000},"page":"1001-1010","source":"Crossref","is-referenced-by-count":179,"title":["Oct4 is required for lineage priming in the developing inner cell mass of the mouse blastocyst"],"prefix":"10.1242","volume":"141","author":[{"given":"Gloryn Chia","family":"Le Bin","sequence":"first","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."},{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Mu\u00f1oz-Descalzo","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA."},{"name":"Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agata","family":"Kurowski","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."},{"name":"Wellcome Trust - Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Leitch","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."},{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghua","family":"Lou","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Mansfield","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Etienne-Dumeau","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Grabole","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Cancer Research UK Gurdon Institute, The Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK."},{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Mulas","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."},{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Niwa","sequence":"additional","affiliation":[{"name":"Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Katerina","family":"Hadjantonakis","sequence":"additional","affiliation":[{"name":"Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10065, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Nichols","sequence":"additional","affiliation":[{"name":"Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK."},{"name":"Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042607535397300_R1","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/emboj.2013.31","article-title":"Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm","volume":"32","author":"Aksoy","year":"2013","journal-title":"EMBO J."},{"key":"2021042607535397300_R2","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ydbio.2010.12.007","article-title":"The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17","volume":"350","author":"Artus","year":"2011","journal-title":"Dev. Biol."},{"key":"2021042607535397300_R3","doi-asserted-by":"crossref","first-page":"3969","DOI":"10.1242\/dev.086025","article-title":"Maternal Cdx2 is dispensable for mouse development","volume":"139","author":"Blij","year":"2012","journal-title":"Development"},{"key":"2021042607535397300_R4","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.cell.2005.08.020","article-title":"Core transcriptional regulatory circuitry in human embryonic stem cells","volume":"122","author":"Boyer","year":"2005","journal-title":"Cell"},{"key":"2021042607535397300_R5","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S0092-8674(03)00392-1","article-title":"Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells","volume":"113","author":"Chambers","year":"2003","journal-title":"Cell"},{"key":"2021042607535397300_R6","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.devcel.2006.02.020","article-title":"Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway","volume":"10","author":"Chazaud","year":"2006","journal-title":"Dev. Cell"},{"key":"2021042607535397300_R7","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1002\/(SICI)1526-968X(200002)26:2<110::AID-GENE2>3.0.CO;2-8","article-title":"Expression of Cre recombinase in mouse oocytes: a means to study maternal effect genes","volume":"26","author":"de Vries","year":"2000","journal-title":"Genesis"},{"key":"2021042607535397300_R8","doi-asserted-by":"crossref","first-page":"4435","DOI":"10.1242\/dev.01316","article-title":"Maternal beta-catenin and E-cadherin in mouse development","volume":"131","author":"de Vries","year":"2004","journal-title":"Development"},{"key":"2021042607535397300_R9","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1126\/science.7809630","article-title":"Requirement of FGF-4 for postimplantation mouse development","volume":"267","author":"Feldman","year":"1995","journal-title":"Science"},{"key":"2021042607535397300_R10","doi-asserted-by":"crossref","first-page":"e4109","DOI":"10.1371\/journal.pone.0004109","article-title":"A novel and critical role for Oct4 as a regulator of the maternal-embryonic transition","volume":"3","author":"Foygel","year":"2008","journal-title":"PLoS ONE"},{"key":"2021042607535397300_R11","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.devcel.2011.10.019","article-title":"Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling","volume":"21","author":"Frankenberg","year":"2011","journal-title":"Dev. Cell"},{"key":"2021042607535397300_R12","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.devcel.2013.05.004","article-title":"Oct4 cell-autonomously promotes primitive endoderm development in the mouse blastocyst","volume":"25","author":"Frum","year":"2013","journal-title":"Dev. Cell"},{"key":"2021042607535397300_R13","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1242\/dev.067702","article-title":"Differential plasticity of epiblast and primitive endoderm precursors within the ICM of the early mouse embryo","volume":"139","author":"Grabarek","year":"2012","journal-title":"Development"},{"key":"2021042607535397300_R14","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.devcel.2010.02.012","article-title":"Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst","volume":"18","author":"Guo","year":"2010","journal-title":"Dev. Cell"},{"key":"2021042607535397300_R15","first-page":"9","article-title":"PAST: Paleontological statistics software package for education and data analysis","volume":"4","author":"Hammer","year":"2001","journal-title":"Palaeontol. Electronica"},{"key":"2021042607535397300_R16","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1242\/dev.084996","article-title":"FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse","volume":"140","author":"Kang","year":"2013","journal-title":"Development"},{"key":"2021042607535397300_R17","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1093\/nar\/gkl050","article-title":"An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis","volume":"34","author":"Kurimoto","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"2021042607535397300_R18","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1095\/biolreprod.104.031757","article-title":"Differential oocyte-specific expression of Cre recombinase activity in GDF-9-iCre, Zp3cre, and Msx2Cre transgenic mice","volume":"71","author":"Lan","year":"2004","journal-title":"Biol. Reprod."},{"key":"2021042607535397300_R19","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S0960-9822(06)00059-5","article-title":"Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line","volume":"7","author":"Lewandoski","year":"1997","journal-title":"Curr. Biol."},{"key":"2021042607535397300_R20","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ydbio.2010.04.020","article-title":"Nanog is required for primitive endoderm formation through a non-cell autonomous mechanism","volume":"344","author":"Messerschmidt","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042607535397300_R21","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0092-8674(03)00393-3","article-title":"The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells","volume":"113","author":"Mitsui","year":"2003","journal-title":"Cell"},{"key":"2021042607535397300_R22","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S0092-8674(00)81769-9","article-title":"Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4","volume":"95","author":"Nichols","year":"1998","journal-title":"Cell"},{"key":"2021042607535397300_R23","doi-asserted-by":"crossref","first-page":"3215","DOI":"10.1242\/dev.038893","article-title":"Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo","volume":"136","author":"Nichols","year":"2009","journal-title":"Development"},{"key":"2021042607535397300_R24","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/74199","article-title":"Quantitative expression of Oct-3\/4 defines differentiation, dedifferentiation or self-renewal of ES cells","volume":"24","author":"Niwa","year":"2000","journal-title":"Nat. Genet."},{"key":"2021042607535397300_R25","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.cell.2005.08.040","article-title":"Interaction between Oct3\/4 and Cdx2 determines trophectoderm differentiation","volume":"123","author":"Niwa","year":"2005","journal-title":"Cell"},{"key":"2021042607535397300_R26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1006\/dbio.1994.1312","article-title":"Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation","volume":"166","author":"Palmieri","year":"1994","journal-title":"Dev. Biol."},{"key":"2021042607535397300_R27","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1242\/dev.021519","article-title":"Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst","volume":"135","author":"Plusa","year":"2008","journal-title":"Development"},{"key":"2021042607535397300_R28","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1530\/jrf.0.0660161","article-title":"Preservation of hamster oocytes to assay the fertilizing capacity of human spermatozoa","volume":"66","author":"Quinn","year":"1982","journal-title":"J. Reprod. Fertil."},{"key":"2021042607535397300_R29","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1242\/dev.038828","article-title":"Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2","volume":"137","author":"Ralston","year":"2010","journal-title":"Development"},{"key":"2021042607535397300_R30","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1093\/nar\/17.1.147","article-title":"Cre-stimulated recombination at loxP-containing DNA sequences placed into the mammalian genome","volume":"17","author":"Sauer","year":"1989","journal-title":"Nucleic Acids Res."},{"key":"2021042607535397300_R31","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1002\/j.1460-2075.1989.tb08392.x","article-title":"A family of octamer-specific proteins present during mouse embryogenesis: evidence for germline-specific expression of an Oct factor","volume":"8","author":"Sch\u00f6ler","year":"1989","journal-title":"EMBO J."},{"key":"2021042607535397300_R32","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.cell.2009.07.039","article-title":"Nanog is the gateway to the pluripotent ground state","volume":"138","author":"Silva","year":"2009","journal-title":"Cell"},{"key":"2021042607535397300_R33","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1073\/pnas.72.12.5099","article-title":"Immunosurgery of mouse blastocyst","volume":"72","author":"Solter","year":"1975","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042607535397300_R34","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/msb.2012.65","article-title":"An Oct4-Sall4-Nanog network controls developmental progression in the pre-implantation mouse embryo","volume":"9","author":"Tan","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"2021042607535397300_R35","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1038\/nprot.2009.236","article-title":"RNA-Seq analysis to capture the transcriptome landscape of a single cell","volume":"5","author":"Tang","year":"2010","journal-title":"Nat. Protoc."},{"key":"2021042607535397300_R36","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1093\/embo-reports\/kve064","article-title":"A highly efficient ligand-regulated Cre recombinase mouse line shows that LoxP recombination is position dependent","volume":"2","author":"Vooijs","year":"2001","journal-title":"EMBO Rep."},{"key":"2021042607535397300_R37","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/ncb2816","article-title":"Establishment of totipotency does not depend on Oct4A","volume":"15","author":"Wu","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"2021042607535397300_R38","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1242\/dev.043471","article-title":"FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst","volume":"137","author":"Yamanaka","year":"2010","journal-title":"Development"},{"key":"2021042607535397300_R39","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nbt780","article-title":"Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture","volume":"21","author":"Ying","year":"2003","journal-title":"Nat. Biotechnol."},{"key":"2021042607535397300_R40","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature06968","article-title":"The ground state of embryonic stem cell self-renewal","volume":"453","author":"Ying","year":"2008","journal-title":"Nature"},{"key":"2021042607535397300_R41","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1101\/gad.9.21.2635","article-title":"Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3","volume":"9","author":"Yuan","year":"1995","journal-title":"Genes Dev."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/141\/5\/1001\/1165816\/1001.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/141\/5\/1001\/1165816\/1001.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,26]],"date-time":"2021-04-26T08:16:29Z","timestamp":1619424989000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/141\/5\/1001\/46587\/Oct4-is-required-for-lineage-priming-in-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3,1]]},"references-count":41,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,3,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.096875","relation":{},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2014,3,1]]}}}