{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:36:12Z","timestamp":1789670172305,"version":"4.0.1"},"reference-count":105,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Joint Special Funds for the Department of Science and Technology of Yunnan Province\u2014Kunming Medical University","award":["202301AY070001-055"],"award-info":[{"award-number":["202301AY070001-055"]}]},{"name":"Joint Special Funds for the Department of Science and Technology of Yunnan Province\u2014Kunming Medical University","award":["2023J0233"],"award-info":[{"award-number":["2023J0233"]}]},{"name":"Scientific Research Fund of Yunnan Provincial Education Commission","award":["202301AY070001-055"],"award-info":[{"award-number":["202301AY070001-055"]}]},{"name":"Scientific Research Fund of Yunnan Provincial Education Commission","award":["2023J0233"],"award-info":[{"award-number":["2023J0233"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JDB"],"abstract":"<jats:p>In recent years, assisted reproductive technology (ART) has developed rapidly with the delay in reproductive age and the rise in infertility rates. During ART, blastocyst quality is a key factor affecting the rate of implantation and clinical pregnancy, and blastocyst formation is dependent on the precise regulation of multiple signaling pathways in preimplantation embryo development. In this review, we systematically analyze the molecular mechanisms of the core pathways, including Hippo, Wnt\/\u03b2-catenin, FGF, Nodal, and BMP, in blastocyst lineage differentiation and morphogenesis, and assess the feasibility of optimizing in vitro culture by targeting key signaling nodes, as well as provide theoretical support for constructing research models of preimplantation embryos.<\/jats:p>","DOI":"10.3390\/jdb13030033","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T12:15:17Z","timestamp":1757420117000},"page":"33","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Signaling Pathways in Human Blastocyst Development: From Molecular Mechanisms to In Vitro Optimization"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0450-9143","authenticated-orcid":false,"given":"Yan","family":"Jiao","sequence":"first","affiliation":[{"name":"School of Life Sciences, Yunnan Normal University, Kunming 650500, China"},{"name":"College of Life Sciences, Southwest United Graduate School, Kunming 650092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiapeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Medical School, Kunming University of Science and Technology, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congge","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650500, China"},{"name":"Yunnan Key Laboratory of Primate Biomedical Research, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexin","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Humanities and Management, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjun","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Yunnan Normal University, Kunming 650500, China"},{"name":"Yunnan International Joint R&D Center for Sustainable Development and Utilization of Biological Resources, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.cca.2020.05.039","article-title":"Biochemistry of infertility","volume":"508","author":"Wasilewski","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1093\/humupd\/dmv016","article-title":"Infertility around the globe: New thinking on gender, reproductive technologies and global movements in the 21st century","volume":"21","author":"Inhorn","year":"2015","journal-title":"Hum. Reprod. Update"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/dmcn.15332","article-title":"Assisted reproductive technology: Short- and long-term outcomes","volume":"65","author":"Graham","year":"2023","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.fertnstert.2018.03.008","article-title":"First in vitro fertilization baby-this is how it happened","volume":"110","author":"Fishel","year":"2018","journal-title":"Fertil. Steril."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/humrep\/deaa055","article-title":"The demographics of assisted reproductive technology births in a Nordic country","volume":"35","author":"Goisis","year":"2020","journal-title":"Hum. Reprod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"171","DOI":"10.23736\/S0031-0808.22.04680-8","article-title":"Oocyte quality and embryo selection strategies: A review for the embryologists, by the embryologists","volume":"64","author":"Anagnostopoulou","year":"2022","journal-title":"Panminerva Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103068","DOI":"10.1016\/j.arcmed.2024.103068","article-title":"Making and Selecting the Best Embryo in In vitro Fertilization","volume":"55","author":"Santamaria","year":"2024","journal-title":"Arch. Med. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1016\/S0015-0282(00)00518-5","article-title":"Blastocyst score affects implantation and pregnancy outcome: Towards a single blastocyst transfer","volume":"73","author":"Gardner","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R103","DOI":"10.1530\/REP-22-0144","article-title":"Cross-species comparison of mouse and human preimplantation development with an emphasis on lineage specification","volume":"165","author":"Biondic","year":"2023","journal-title":"Reproduction"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"203752","DOI":"10.1016\/j.cdev.2021.203752","article-title":"A theoretical understanding of mammalian preimplantation development","volume":"168","year":"2021","journal-title":"Cells Dev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1093\/humupd\/dmz008","article-title":"The enigmatic morula: Mechanisms of development, cell fate determination, self-correction and implications for ART","volume":"25","author":"Coticchio","year":"2019","journal-title":"Hum. Reprod. Update"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.rbmo.2019.06.009","article-title":"Controversies in ART: Can the IVF laboratory influence preimplantation embryo aneuploidy?","volume":"39","author":"Swain","year":"2019","journal-title":"Reprod. Biomed. Online"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bari, M.W., Ishiyama, S., Matsumoto, S., Mochizuki, K., and Kishigami, S. (2022). From lessons on the long-term effects of the preimplantation environment on later health to a \u201cmodified ART-DOHaD\u201d animal model. Reprod. Med. Biol., 21.","DOI":"10.1002\/rmb2.12469"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s10735-024-10338-7","article-title":"Signaling pathway regulators in preimplantation embryos","volume":"56","author":"Karami","year":"2024","journal-title":"J. Mol. Histol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.devcel.2015.10.011","article-title":"Lineage-Specific Profiling Delineates the Emergence and Progression of Naive Pluripotency in Mammalian Embryogenesis","volume":"35","author":"Boroviak","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4349","DOI":"10.1111\/j.1742-4658.2007.05980.x","article-title":"Signaling pathways and preimplantation development of mammalian embryos","volume":"274","author":"Zhang","year":"2007","journal-title":"FEBS J."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Lee, S.H., and Rinaudo, P.F. (2024). Metabolic regulation of preimplantation embryo development in vivo and in vitro: Molecular mechanisms and insights. Biochem. Biophys. Res. Commun., 726.","DOI":"10.1016\/j.bbrc.2024.150256"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"102125","DOI":"10.1016\/j.gde.2023.102125","article-title":"An update on human pre- and peri-implantation development: A blueprint for blastoids","volume":"83","author":"David","year":"2023","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"dev167833","DOI":"10.1242\/dev.167833","article-title":"Single cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development","volume":"145","author":"Boroviak","year":"2018","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1146\/annurev-cellbio-100913-013027","article-title":"Zygotic genome activation during the maternal-to-zygotic transition","volume":"30","author":"Lee","year":"2014","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.theriogenology.2023.06.017","article-title":"Maternal Kdm2a-mediated PI3K\/Akt signaling and E-cadherin stimulate the morula-to-blastocyst transition revealing crucial roles in early embryonic development","volume":"209","author":"Xiong","year":"2023","journal-title":"Theriogenology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1016\/j.cell.2018.02.035","article-title":"Expanding Actin Rings Zipper the Mouse Embryo for Blastocyst Formation","volume":"173","author":"Zenker","year":"2018","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41586-019-1309-x","article-title":"Hydraulic control of mammalian embryo size and cell fate","volume":"571","author":"Chan","year":"2019","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.theriogenology.2023.10.011","article-title":"Effect of blastocyst development on hatching and embryo implantation","volume":"214","author":"Ma","year":"2024","journal-title":"Theriogenology"},{"key":"ref_25","first-page":"8","article-title":"Blastocyst Hatching in Humans","volume":"48","author":"Shafei","year":"2017","journal-title":"Ontogenez"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1242\/dev.128314","article-title":"Lineage specification in the mouse preimplantation embryo","volume":"143","author":"Chazaud","year":"2016","journal-title":"Development"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1093\/molehr\/gau027","article-title":"Totipotency and lineage segregation in the human embryo","volume":"20","author":"Krivega","year":"2014","journal-title":"Mol. Hum. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/bs.ctdb.2017.11.004","article-title":"Human Pre-gastrulation Development","volume":"128","author":"Wamaitha","year":"2018","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/s41586-020-2759-x","article-title":"Initiation of a conserved trophectoderm program in human, cow and mouse embryos","volume":"587","author":"Gerri","year":"2020","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"dev201112","DOI":"10.1242\/dev.201112","article-title":"A conserved role of the Hippo signalling pathway in initiation of the first lineage specification event across mammals","volume":"150","author":"Gerri","year":"2023","journal-title":"Development"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1093\/molehr\/gav036","article-title":"WNT3 and membrane-associated \u03b2-catenin regulate trophectoderm lineage differentiation in human blastocysts","volume":"21","author":"Krivega","year":"2015","journal-title":"Mol. Hum. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.ydbio.2011.10.030","article-title":"Human hypoblast formation is not dependent on FGF signalling","volume":"361","author":"Roode","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/j.stem.2024.05.003","article-title":"Naive pluripotent stem cell-based models capture FGF-dependent human hypoblast lineage specification","volume":"31","author":"Dattani","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1093\/humrep\/det400","article-title":"Treatment of human embryos with the TGF\u03b2 inhibitor SB431542 increases epiblast proliferation and permits successful human embryonic stem cell derivation","volume":"29","author":"Heindryckx","year":"2014","journal-title":"Hum. Reprod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.devcel.2024.10.020","article-title":"Initiation and maintenance of the pluripotent epiblast in pre-implantation human development is independent of NODAL signaling","volume":"60","author":"Brumm","year":"2025","journal-title":"Dev. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/mrd.23081","article-title":"BMP4 plays a role in apoptosis during human preimplantation development","volume":"86","author":"Aberkane","year":"2019","journal-title":"Mol. Reprod. Dev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S0092-8674(03)00557-9","article-title":"The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis","volume":"114","author":"Harvey","year":"2003","journal-title":"Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0092-8674(03)00549-X","article-title":"hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts","volume":"114","author":"Wu","year":"2003","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Juan, W.C., and Hong, W. (2016). Targeting the Hippo Signaling Pathway for Tissue Regeneration and Cancer Therapy. Genes, 7.","DOI":"10.3390\/genes7090055"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.cell.2015.10.044","article-title":"Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer","volume":"163","author":"Yu","year":"2015","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s00441-021-03530-8","article-title":"Cell fate determination and Hippo signaling pathway in preimplantation mouse embryo","volume":"386","author":"Yildirim","year":"2021","journal-title":"Cell Tissue Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1038\/ncomms3251","article-title":"Angiomotin prevents pluripotent lineage differentiation in mouse embryos via Hippo pathway-dependent and -independent mechanisms","volume":"4","author":"Leung","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/j.cub.2013.05.014","article-title":"Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos","volume":"23","author":"Hirate","year":"2013","journal-title":"Curr. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.devcel.2014.06.019","article-title":"Notch and hippo converge on Cdx2 to specify the trophectoderm lineage in the mouse blastocyst","volume":"30","author":"Rayon","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.semcdb.2015.09.006","article-title":"Towards understanding the roles of position and geometry on cell fate decisions during preimplantation development","volume":"47\u201348","author":"Biggins","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/j.cub.2013.05.044","article-title":"The Hippo pathway member Nf2 is required for inner cell mass specification","volume":"23","author":"Cockburn","year":"2013","journal-title":"Curr. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.mod.2007.11.002","article-title":"Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos","volume":"125","author":"Nishioka","year":"2008","journal-title":"Mech. Dev."},{"key":"ref_48","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":"ref_49","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1093\/humrep\/deac138","article-title":"TEAD4 regulates trophectoderm differentiation upstream of CDX2 in a GATA3-independent manner in the human preimplantation embryo","volume":"37","author":"Stamatiadis","year":"2022","journal-title":"Hum. Reprod."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4917","DOI":"10.1038\/s41467-020-18680-6","article-title":"Dynamics and clinical relevance of maternal mRNA clearance during the oocyte-to-embryo transition in humans","volume":"11","author":"Sha","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1093\/humrep\/dead107","article-title":"Lineage segregation in human pre-implantation embryos is specified by YAP1 and TEAD1","volume":"38","author":"Regin","year":"2023","journal-title":"Hum. Reprod."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/S0960-9822(99)80091-8","article-title":"The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell","volume":"9","author":"Hart","year":"1999","journal-title":"Curr. Biol. CB"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Piao, S., Lee, S.H., Kim, H., Yum, S., Stamos, J.L., Xu, Y.B., Lee, S.J., Lee, J., Oh, S., and Han, J.K. (2008). Direct Inhibition of GSK3\u03b2 by the Phosphorylated Cytoplasmic Domain of LRP6 in Wnt\/\u03b2-Catenin Signaling. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0004046"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/382638a0","article-title":"Functional interaction of beta-catenin with the transcription factor LEF-1","volume":"382","author":"Behrens","year":"1996","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Garabedian, M.V., and Good, M.C. (2021). OptoLRP6 Illuminates Wnt Signaling in Early Embryo Development. J. Mol. Biol., 433.","DOI":"10.1016\/j.jmb.2021.167053"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1083\/jcb.148.3.567","article-title":"Requirement for beta-catenin in anterior-posterior axis formation in mice","volume":"148","author":"Huelsken","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1038\/s41467-023-36914-1","article-title":"The Wnt\/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency","volume":"14","author":"Athanasouli","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Sadeghi, M., Andani, M.R., Hajian, M., Sanei, N., Moradi-Hajidavaloo, R., Mahvash, N., Jafarpour, F., and Nasr-Esfahani, M.H. (2023). Developmental competence of IVF and SCNT goat embryos is improved by inhibition of canonical WNT signaling. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0281331"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1093\/jmcb\/mjq029","article-title":"Genome-wide gene expression profiling reveals aberrant MAPK and Wnt signaling pathways associated with early parthenogenesis","volume":"2","author":"Liu","year":"2010","journal-title":"J. Mol. Cell. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Denicol, A.C., Dobbs, K.B., McLean, K.M., Carambula, S.F., Loureiro, B., and Hansen, P.J. (2013). Canonical WNT signaling regulates development of bovine embryos to the blastocyst stage. Sci. Rep., 3.","DOI":"10.1038\/srep01266"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"de Jaime-Soguero, A., Abreu de Oliveira, W.A., and Lluis, F. (2018). The Pleiotropic Effects of the Canonical Wnt Pathway in Early Development and Pluripotency. Genes, 9.","DOI":"10.3390\/genes9020093"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cell.2016.03.023","article-title":"Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos","volume":"165","author":"Petropoulos","year":"2016","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1016\/j.scib.2025.05.003","article-title":"Persistent Wnt signaling affects IVF embryo implantation and offspring metabolism","volume":"70","author":"Jia","year":"2025","journal-title":"Sci. Bull."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/s41588-024-01788-6","article-title":"A single-cell transcriptome atlas of human euploid and aneuploid blastocysts","volume":"56","author":"Wang","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1852","DOI":"10.1038\/s41392-020-00222-7","article-title":"FGF\/FGFR signaling in health and disease","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1387\/ijdb.180408as","article-title":"FGF\/ERK signaling pathway: How it operates in mammalian preimplantation embryos and embryo-derived stem cells","volume":"63","author":"Klimczewska","year":"2019","journal-title":"Int. J. Dev. Biol."},{"key":"ref_67","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":"ref_68","doi-asserted-by":"crossref","unstructured":"Goissis, M.D., Bradshaw, B., Posfai, E., and Rossant, J. (2023). Influence of FGF4 and BMP4 on FGFR2 dynamics during the segregation of epiblast and primitive endoderm cells in the pre-implantation mouse embryo. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0279515"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Krawczyk, K., Wilczak, K., Szczepa\u0144ska, K., Maleszewski, M., and Suwi\u0144ska, A. (2022). Paracrine interactions through FGFR1 and FGFR2 receptors regulate the development of preimplantation mouse chimaeric embryo. Open Biol., 12.","DOI":"10.1098\/rsob.220193"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.devcel.2017.05.004","article-title":"Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency","volume":"41","author":"Molotkov","year":"2017","journal-title":"Dev. Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1101\/gad.257071.114","article-title":"Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells","volume":"29","author":"Wamaitha","year":"2015","journal-title":"Genes Dev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.ydbio.2013.09.008","article-title":"Allocation of inner cells to epiblast vs primitive endoderm in the mouse embryo is biased but not determined by the round of asymmetric divisions (8\u219216- and 16\u219232-cells)","volume":"385","author":"Krupa","year":"2014","journal-title":"Dev. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"13463","DOI":"10.1038\/ncomms13463","article-title":"Asynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst","volume":"7","author":"Saiz","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e56079","DOI":"10.7554\/eLife.56079","article-title":"Growth-factor-mediated coupling between lineage size and cell fate choice underlies robustness of mammalian development","volume":"9","author":"Saiz","year":"2020","journal-title":"eLife"},{"key":"ref_75","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":"ref_76","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":"ref_77","doi-asserted-by":"crossref","unstructured":"Cang, Z., Wang, Y., Wang, Q., Cho, K.W.Y., Holmes, W., and Nie, Q. (2021). A multiscale model via single-cell transcriptomics reveals robust patterning mechanisms during early mammalian embryo development. PLoS Comput. Biol., 17.","DOI":"10.1371\/journal.pcbi.1008571"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1017\/S0967199419000753","article-title":"The effect of dual inhibition of Ras-MEK-ERK and GSK3\u03b2 pathways on development of in vitro cultured rabbit embryos","volume":"28","author":"Bontovics","year":"2020","journal-title":"Zygote"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1242\/dev.071688","article-title":"The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos","volume":"139","author":"Kuijk","year":"2012","journal-title":"Development"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez, A., Allegrucci, C., and Alberio, R. (2012). Modulation of pluripotency in the porcine embryo and iPS cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049079"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"27678","DOI":"10.1074\/jbc.272.44.27678","article-title":"TbetaRI phosphorylation of Smad2 on Ser465 and Ser467 is required for Smad2-Smad4 complex formation and signaling","volume":"272","author":"Abdollah","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/S1097-2765(01)00417-8","article-title":"Structural basis of Smad1 activation by receptor kinase phosphorylation","volume":"8","author":"Qin","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1101\/gad.11.8.984","article-title":"The TGF-beta family mediator Smad1 is phosphorylated directly and activated functionally by the BMP receptor kinase","volume":"11","author":"Kretzschmar","year":"1997","journal-title":"Genes. Dev."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1242\/dev.091769","article-title":"Activin\/Nodal signalling in stem cells","volume":"142","author":"Pauklin","year":"2015","journal-title":"Development"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1093\/abbs\/gmx128","article-title":"Molecular regulation of Nodal signaling during mesendoderm formation","volume":"50","author":"Wei","year":"2018","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Papanayotou, C., and Collignon, J. (2014). Activin\/Nodal signalling before implantation: Setting the stage for embryo patterning. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369.","DOI":"10.1098\/rstb.2013.0539"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.ydbio.2010.10.036","article-title":"Nodal cis-regulatory elements reveal epiblast and primitive endoderm heterogeneity in the peri-implantation mouse embryo","volume":"349","author":"Granier","year":"2011","journal-title":"Dev. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/s13287-020-1588-z","article-title":"A cytokine screen using CRISPR-Cas9 knock-in reporter pig iPS cells reveals that Activin A regulates NANOG","volume":"11","author":"Xu","year":"2020","journal-title":"Stem Cell. Res. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/j.stem.2021.04.001","article-title":"Principles of signaling pathway modulation for enhancing human naive pluripotency induction","volume":"28","author":"Bayerl","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e67259","DOI":"10.7554\/eLife.67259","article-title":"TGF\u03b2 signalling is required to maintain pluripotency of human na\u00efve pluripotent stem cells","volume":"10","author":"Osnato","year":"2021","journal-title":"eLife"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1002\/dvg.20614","article-title":"Three inhibitors of FGF receptor, ERK, and GSK3 establishes germline-competent embryonic stem cells of C57BL\/6N mouse strain with high efficiency and stability","volume":"48","author":"Kiyonari","year":"2010","journal-title":"Genesis"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Zinski, J., Tajer, B., and Mullins, M.C. (2018). TGF-\u03b2 Family Signaling in Early Vertebrate Development. Cold Spring Harb. Perspect. Biol., 10.","DOI":"10.1101\/cshperspect.a033274"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4976","DOI":"10.1038\/s41467-024-49065-8","article-title":"Molecular mechanism of BMP signal control by Twisted gastrulation","volume":"15","author":"Malinauskas","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"5667","DOI":"10.1038\/ncomms6667","article-title":"BMP signalling regulates the pre-implantation development of extra-embryonic cell lineages in the mouse embryo","volume":"5","author":"Graham","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s00018-022-04478-w","article-title":"The role of BMP4 signaling in trophoblast emergence from pluripotency","volume":"79","author":"Roberts","year":"2022","journal-title":"Cell Mol. Life Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ydbio.2014.10.001","article-title":"BMP signaling is required for cell cleavage in preimplantation-mouse embryos","volume":"397","author":"Luong","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"836","DOI":"10.4161\/cc.3.7.956","article-title":"p53 moves to mitochondria: A turn on the path to apoptosis","volume":"3","author":"Murphy","year":"2004","journal-title":"Cell Cycle"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1095\/biolreprod63.5.1413","article-title":"Anti-apoptotic action of insulin-like growth factor-I during human preimplantation embryo development","volume":"63","author":"Spanos","year":"2000","journal-title":"Biol. Reprod."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"6566","DOI":"10.1016\/j.cell.2024.08.048","article-title":"mTOR activity paces human blastocyst stage developmental progression","volume":"187","author":"Iyer","year":"2024","journal-title":"Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.stemcr.2019.06.003","article-title":"Elevated Exogenous Pyruvate Potentiates Mesodermal Differentiation through Metabolic Modulation and AMPK\/mTOR Pathway in Human Embryonic Stem Cells","volume":"13","author":"Song","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ydbio.2005.05.033","article-title":"The PI3K\/Akt pathway is present and functional in the preimplantation mouse embryo","volume":"284","author":"Riley","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1002\/mrd.20212","article-title":"Mouse embryonic stem cells and preimplantation embryos require signaling through the phosphatidylinositol 3-kinase pathway to suppress apoptosis","volume":"70","author":"Gross","year":"2005","journal-title":"Mol. Reprod. Dev."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/s41586-018-0150-y","article-title":"Self-organization of a human organizer by combined Wnt and Nodal signalling","volume":"558","author":"Martyn","year":"2018","journal-title":"Nature"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.devcel.2006.07.005","article-title":"The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4","volume":"11","author":"Lu","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"dev172791","DOI":"10.1242\/dev.172791","article-title":"A wave of WNT signaling balanced by secreted inhibitors controls primitive streak formation in micropattern colonies of human embryonic stem cells","volume":"146","author":"Martyn","year":"2019","journal-title":"Development"}],"container-title":["Journal of Developmental Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2221-3759\/13\/3\/33\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:42:29Z","timestamp":1760035349000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2221-3759\/13\/3\/33"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,9]]},"references-count":105,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["jdb13030033"],"URL":"https:\/\/doi.org\/10.3390\/jdb13030033","relation":{},"ISSN":["2221-3759"],"issn-type":[{"value":"2221-3759","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,9]]}}}