{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T21:47:51Z","timestamp":1790027271588,"version":"4.0.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T00:00:00Z","timestamp":1660608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>Implantation of the blastocyst into the uterus is a specific and essential process for mammalian embryonic development. In mice, implantation is initiated from the mural trophectoderm of the blastocyst and the mTE controls implantation progression by acquiring the ability to attach and invade into the endometrium while differentiating into primary trophoblast giant cells. Nevertheless, it remains largely unclear when and how the mTE differentiates and acquires this ability during implantation. Here, by RNA sequencing analysis with the pre- and peri-implantation mTE, we show that the mTE undergoes stage-specific and dynamic changes of gene expression during implantation. We also reveal that the mTE begins down-regulating <jats:italic>Cdx2<\/jats:italic> and up-regulating differentiation marker genes during the peri-implantation stage. In addition, using trophectoderm (TE) -specific lentiviral vector-mediated gene transduction, we demonstrate that TE-specific <jats:italic>Cdx2<\/jats:italic> overexpression represses differentiation of the mTE into the primary trophoblast giant cells. Moreover, we reveal that TE-specific <jats:italic>Cdx2<\/jats:italic> overexpression also represses the up-regulation of cell adhesion- and migration-related genes, including <jats:italic>Slc6a14<\/jats:italic>, <jats:italic>Slc16a3<\/jats:italic>, <jats:italic>Itga7<\/jats:italic>, <jats:italic>Itgav<\/jats:italic> and <jats:italic>Itgb3<\/jats:italic>, which are known to regulate migration of trophectoderm\u00a0cells. In particular, the expression of <jats:italic>Itgb3<\/jats:italic>, an integrin subunit gene, exhibits high inverse correlation with that of <jats:italic>Cdx2<\/jats:italic> in the TE. Reflecting the down-regulation of the genes for TE migration, TE-specific <jats:italic>Cdx2<\/jats:italic> overexpression causes suppression of the blastocyst outgrowth <jats:italic>in vitro<\/jats:italic> and abnormal progression of implantation <jats:italic>in vivo<\/jats:italic>. Thus, our results specify the time-course changes of global gene expression in the mTE during implantation and uncover the significance of <jats:italic>Cdx2<\/jats:italic> down-regulation for implantation progression.<\/jats:p>","DOI":"10.3389\/fcell.2022.945241","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T07:55:41Z","timestamp":1660636541000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Dynamic Changes of Gene Expression in Mouse Mural Trophectoderm Regulated by Cdx2 During Implantation"],"prefix":"10.3389","volume":"10","author":[{"given":"Daisuke","family":"Suzuki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Kumamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidehiko","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,16]]},"reference":[{"key":"B52","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.molcel.2013.09.002","article-title":"Context-Dependent Wiring of Sox2 Regulatory Networks for Self-Renewal of Embryonic and Trophoblast Stem Cells","volume":"52","author":"Adachi","year":"2013","journal-title":"Mol. Cell"},{"key":"B1","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.ydbio.2005.02.009","article-title":"Blastocysts Don't Go it Alone. Extrinsic Signals Fine-Tune the Intrinsic Developmental Program of Trophoblast Cells","volume":"280","author":"Armant","year":"2005","journal-title":"Dev. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.ydbio.2006.03.006","article-title":"Post-Implantation Mouse Conceptuses Produce Paracrine Signals that Regulate the Uterine Endometrium Undergoing Decidualization","volume":"294","author":"Bany","year":"2006","journal-title":"Dev. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1038\/nm.3012","article-title":"Mechanisms of Implantation: Strategies for Successful Pregnancy","volume":"18","author":"Cha","year":"2012","journal-title":"Nat. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e48933","DOI":"10.1371\/journal.pone.0048933","article-title":"Estrogen-dependent Uterine Secretion of Osteopontin Activates Blastocyst Adhesion Competence","volume":"7","author":"Chaen","year":"2012","journal-title":"PLoS One"},{"key":"B5","doi-asserted-by":"publisher","first-page":"180081","DOI":"10.1098\/rsob.180081","article-title":"Exploring the Links between Cancer and Placenta Development","volume":"8","author":"Costanzo","year":"2018","journal-title":"Open Biol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1210\/er.2003-0020","article-title":"Molecular Cues to Implantation","volume":"25","author":"Dey","year":"2004","journal-title":"Endocr. Rev."},{"key":"B7","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/s12522-013-0153-1","article-title":"Uterine Receptivity and Embryo-Uterine Interactions in Embryo Implantation: Lessons from Mice","volume":"12","author":"Egashira","year":"2013","journal-title":"Reprod. Med. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1242\/dev.33.4.1067","article-title":"Epithelial Autolysis during Implantation of the Mouse Blastocyst: an Ultrastructural Study","volume":"33","author":"El-Shershaby","year":"1975","journal-title":"J. Embryol. Exp. Morphol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1002\/bies.201400155","article-title":"Lactate Production by the Mammalian Blastocyst: Manipulating the Microenvironment for Uterine Implantation and Invasion?","volume":"37","author":"Gardner","year":"2015","journal-title":"Bioessays"},{"key":"B10","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.ydbio.2011.10.021","article-title":"Leucine and Arginine Regulate Trophoblast Motility through mTOR-dependent and Independent Pathways in the Preimplantation Mouse Embryo","volume":"361","author":"Gonz\u00e1lez","year":"2012","journal-title":"Dev. Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3276","DOI":"10.1016\/j.devcel.2021.10.014","article-title":"3D Biomimetic Platform Reveals the First Interactions of the Embryo and the Maternal Blood Vessels","volume":"56","author":"Govindasamy","year":"2021","journal-title":"Dev. Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/sj.onc.1210601","article-title":"The Intestine-specific Homeobox Gene Cdx2 Decreases Mobility and Antagonizes Dissemination of Colon Cancer Cells","volume":"27","author":"Gross","year":"2008","journal-title":"Oncogene"},{"key":"B13","doi-asserted-by":"publisher","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":"B14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41576-019-0169-4","article-title":"Mechanisms of Early Placental Development in Mouse and Humans","volume":"21","author":"Hemberger","year":"2020","journal-title":"Nat. Rev. Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/s0025-6196(11)60669-1","article-title":"Cancer and Pregnancy: Parallels in Growth, Invasion, and Immune Modulation and Implications for Cancer Therapeutic Agents","volume":"84","author":"Holtan","year":"2009","journal-title":"Mayo Clin. Proc."},{"key":"B16","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1387\/ijdb.082768dh","article-title":"Development and Function of Trophoblast Giant Cells in the Rodent Placenta","volume":"54","author":"Hu","year":"2010","journal-title":"Int. J. Dev. Biol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/s0092-8674(02)00971-6","article-title":"Integrins","volume":"110","author":"Hynes","year":"2002","journal-title":"Cell"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1095\/biolreprod62.5.1285","article-title":"Blockade of the \u03b1v\u03b23 Integrin Adversely Affects Implantation in the Mouse1","volume":"62","author":"Illera","year":"2000","journal-title":"Biol. Reprod."},{"key":"B19","doi-asserted-by":"publisher","first-page":"2865","DOI":"10.4161\/cc.10.17.17188","article-title":"Tracking the Intermediate Stages of Epithelial-Mesenchymal Transition in Epithelial Stem Cells and Cancer","volume":"10","author":"Jordan","year":"2011","journal-title":"Cell Cycle"},{"key":"B20","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1006\/dbio.2001.0404","article-title":"Trophoblast-Specific Expression and Function of the Integrin \u03b17 Subunit in the Peri-Implantation Mouse Embryo","volume":"239","author":"Klaffky","year":"2001","journal-title":"Dev. Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"7776","DOI":"10.1038\/ncomms8776","article-title":"Fgf and Esrrb Integrate Epigenetic and Transcriptional Networks that Regulate Self-Renewal of Trophoblast Stem Cells","volume":"6","author":"Latos","year":"","journal-title":"Nat. Commun."},{"key":"B53","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1101\/gad.268821.115","article-title":"Elf5-Centered Transcription Factor Hub Controls Trophoblast Stem Cell Self-Renewal and Differentiation Through Stoichiometry-Sensitive Shifts in Target Gene Networks","volume":"29","author":"Latos","year":"","journal-title":"Genes Dev."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.1242\/dev.133462","article-title":"From the Stem of the Placental Tree: Trophoblast Stem Cells and Their Progeny","volume":"143","author":"Latos","year":"2016","journal-title":"Development"},{"key":"B23","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.celrep.2015.03.035","article-title":"Entosis Allows Timely Elimination of the Luminal Epithelial Barrier for Embryo Implantation","volume":"11","author":"Li","year":"2015","journal-title":"Cell Rep."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.1242\/dev.054775","article-title":"Klf5 Regulates Lineage Formation in the Pre-implantation Mouse Embryo","volume":"137","author":"Lin","year":"2010","journal-title":"Development"},{"key":"B25","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1262\/jrd.2017-047","article-title":"Molecular and Cellular Events during Blastocyst Implantation in the Receptive Uterus: Clues from Mouse Models","volume":"63","author":"Matsumoto","year":"2017","journal-title":"J. Reproduction Dev."},{"key":"B26","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.ydbio.2014.04.023","article-title":"Cited2 Is Required in Trophoblasts for Correct Placental Capillary Patterning","volume":"392","author":"Moreau","year":"2014","journal-title":"Dev. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e60","DOI":"10.1093\/nar\/gkv134","article-title":"SC3-seq: a Method for Highly Parallel and Quantitative Measurement of Single-Cell Gene Expression","volume":"43","author":"Nakamura","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B28","doi-asserted-by":"publisher","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":"B29","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1056\/NEJMra000763","article-title":"Implantation and the Survival of Early Pregnancy","volume":"345","author":"Norwitz","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1089\/cell.2014.0073","article-title":"Deficiency of Genomic Reprogramming in Trophoblast Stem Cells Following Nuclear Transfer","volume":"17","author":"Ogawa","year":"2015","journal-title":"Cell. Reprogr."},{"key":"B31","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nbt1280","article-title":"Complementation of Placental Defects and Embryonic Lethality by Trophoblast-specific Lentiviral Gene Transfer","volume":"25","author":"Okada","year":"2007","journal-title":"Nat. Biotechnol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.ydbio.2019.07.008","article-title":"Esrrb Function is Required for Proper Primordial Germ Cell Development in Presomite Stage Mouse Embryos","volume":"455","author":"Okamura","year":"2019","journal-title":"Dev. Biol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1095\/biolreprod36.1.211","article-title":"Apoptosis as the Mode of Uterine Epithelial Cell Death during Embryo Implantation in Mice and Rats1","volume":"36","author":"Parr","year":"1987","journal-title":"Biol. Reprod."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.22906","article-title":"Position- and Hippo Signaling-dependent Plasticity during Lineage Segregation in the Early Mouse Embryo","volume":"6","author":"Posfai","year":"2017","journal-title":"Elife"},{"key":"B34","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1038\/ng0398-271","article-title":"The Hand1 bHLH Transcription Factor Is Essential for Placentation and Cardiac Morphogenesis","volume":"18","author":"Riley","year":"1998","journal-title":"Nat. Genet."},{"key":"B35","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1242\/dev.017178","article-title":"Blastocyst Lineage Formation, Early Embryonic Asymmetries and axis Patterning in the Mouse","volume":"136","author":"Rossant","year":"2009","journal-title":"Development"},{"key":"B36","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.ydbio.2003.12.010","article-title":"\u03b15\u03b21, \u03b1V\u03b23 and the Platelet-Associated Integrin \u03b1IIb\u03b23 Coordinately Regulate Adhesion and Migration of Differentiating Mouse Trophoblast Cells","volume":"268","author":"Rout","year":"2004","journal-title":"Dev. Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"e202000674","DOI":"10.26508\/lsa.202000674","article-title":"MicroRNA Regulation of Murine Trophoblast Stem Cell Self-Renewal and Differentiation","volume":"3","author":"Saha","year":"2020","journal-title":"Life Sci. Alliance"},{"key":"B38","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"B39","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1128\/mcb.20.2.530-541.2000","article-title":"The HAND1 Basic Helix-Loop-Helix Transcription Factor Regulates Trophoblast Differentiation via Multiple Mechanisms","volume":"20","author":"Scott","year":"2000","journal-title":"Mol. Cell Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1242\/dev.01801","article-title":"Cdx2 Is Required for Correct Cell Fate Specification and Differentiation of Trophectoderm in the Mouse Blastocyst","volume":"132","author":"Strumpf","year":"2005","journal-title":"Development"},{"key":"B41","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/s0012-1606(03)00130-1","article-title":"Mechanisms of Implantation in the Mouse: Differentiation and Functional Importance of Trophoblast Giant Cell Behavior","volume":"258","author":"Sutherland","year":"2003","journal-title":"Dev. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1089\/scd.2018.0068","article-title":"The Differentiation Potency of Trophoblast Stem Cells from Mouse Androgenetic Embryos","volume":"28","author":"Suzuki","year":"2019","journal-title":"Stem Cells Dev."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e12446","DOI":"10.1002\/rmb2.12446","article-title":"CDX2 Downregulation in Mouse Mural Trophectoderm during Peri\u2010implantation Is Heteronomous, Dependent on the YAP\u2010TEAD Pathway and Controlled by Estrogen\u2010induced Factors","volume":"21","author":"Suzuki","year":"2022","journal-title":"Reprod Med. Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"2072","DOI":"10.1126\/science.282.5396.2072","article-title":"Promotion of Trophoblast Stem Cell Proliferation by FGF4","volume":"282","author":"Tanaka","year":"1998","journal-title":"Science"},{"key":"B45","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1186\/1747-1028-4-10","article-title":"Cip\/Kip Cyclin-dependent Protein Kinase Inhibitors and the Road to Polyploidy","volume":"4","author":"Ullah","year":"2009","journal-title":"Cell Div."},{"key":"B46","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1093\/humupd\/dmi044","article-title":"System B0,+ Amino Acid Transport Regulates the Penetration Stage of Blastocyst Implantation with Possible Long-Term Developmental Consequences through Adulthood","volume":"12","author":"Van Winkle","year":"2006","journal-title":"Hum. Reprod. Update"},{"key":"B47","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s12935-019-1066-9","article-title":"Over-expression of CDX2 Alleviates Breast Cancer by Up-Regulating microRNA Let-7b and Inhibiting COL11A1 Expression","volume":"20","author":"Wang","year":"2020","journal-title":"Cancer Cell Int."},{"key":"B48","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1159\/000066970","article-title":"Integrin-mediated Adhesion and Signaling during Blastocyst Implantation","volume":"172","author":"Wang","year":"2002","journal-title":"Cells Tissues Organs"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e1004618","DOI":"10.1371\/journal.pgen.1004618","article-title":"HIPPO Pathway Members Restrict SOX2 to the Inner Cell Mass where it Promotes ICM Fates in the Mouse Blastocyst","volume":"10","author":"Wicklow","year":"2014","journal-title":"PLoS Genet."},{"key":"B50","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.ydbio.2006.02.025","article-title":"Loss of Cited2 Affects Trophoblast Formation and Vascularization of the Mouse Placenta","volume":"294","author":"Withington","year":"2006","journal-title":"Dev. Biol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1038\/s41416-020-01148-1","article-title":"CDX2 Inhibits Epithelial-Mesenchymal Transition in Colorectal Cancer by Modulation of Snail Expression and \u03b2-catenin Stabilisation via Transactivation of PTEN Expression","volume":"124","author":"Yu","year":"2021","journal-title":"Br. J. Cancer"}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.945241\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T07:55:44Z","timestamp":1660636544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2022.945241\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,16]]},"references-count":54,"alternative-id":["10.3389\/fcell.2022.945241"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2022.945241","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,16]]},"article-number":"945241"}}