title: The dual roles of geminin during trophoblast proliferation and differentiation.
abstract: Geminin is a protein involved in both DNA replication and cell fate acquisition. Although it is essential for mammalian preimplantation development, its role remains unclear. In one study, ablation of the geminin gene (Gmnn) in mouse preimplantation embryos resulted in apoptosis, suggesting that geminin prevents DNA re-replication, whereas in another study it resulted in differentiation of blastomeres into trophoblast giant cells (TGCs), suggesting that geminin regulates trophoblast specification and differentiation. Other studies concluded that trophoblast differentiation into TGCs is regulated by fibroblast growth factor-4 (FGF4), and that geminin is required to maintain endocycles. Here we show that ablation of Gmnn in trophoblast stem cells (TSCs) proliferating in the presence of FGF4 closely mimics the events triggered by FGF4 deprivation: arrest of cell proliferation, formation of giant cells, excessive DNA replication in the absence of DNA damage and apoptosis, and changes in gene expression that include loss of Chk1 with up-regulation of p57 and p21. Moreover, FGF4 deprivation of TSCs reduces geminin to a basal level that is required for maintaining endocycles in TGCs. Thus, geminin acts both like a component of the FGF4 signal transduction pathway that governs trophoblast proliferation and differentiation, and geminin is required to maintain endocycles.
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892-2753, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: de Renty
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892-2753, USA.
authors.forename: Kotaro J
authors.initials: KJ
authors.lastname: Kaneko
authors.affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892-2753, USA. Electronic address: depamphm@mail.nih.gov.
authors.forename: Melvin L
authors.initials: ML
authors.lastname: DePamphilis
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000096:biosynthesis; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D051519:Fibroblast Growth Factor 4 / Q000235:genetics / Q000378:metabolism*; D064248:Geminin / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015726:Giant Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C493965:Cdkn1c protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050761:Cyclin-Dependent Kinase Inhibitor p57; C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D064248:Geminin; C577997:Gmnn protein, mouse; D034741:RNA, Small Interfering; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse
keywords: Cdkn1a/p21/Cip1; Cdkn1c/p57/Kip2; Chk1; Differentiation; Endocycles; Endoreplication; Geminin; Trophectoderm; Trophoblast giant cells; Trophoblast stem cells