Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development.

In multicellular eukaryotes, geminin prevents overreplication of DNA in proliferating cells. Here, we show that genetic ablation of geminin in the mouse prevents formation of inner cell mass (ICM) and causes premature endoreduplication at eight cells, rather than 32 cells. All cells in geminin-deficient embryos commit to the trophoblast cell lineage and consist of trophoblast giant cells (TGCs) only. Geminin is also down-regulated in TGCs of wild-type blastocysts during S and gap-like phases by proteasome-mediated degradation, suggesting that loss of geminin is part of the mechanism regulating endoreduplication.

[1]  R. Roberts,et al.  Cdx2 Gene Expression and Trophectoderm Lineage Specification in Mouse Embryos , 2006, Science.

[2]  E. Nigg,et al.  Geminin Regulates Multiple Steps of the Chromosome Inheritance Cycle , 2006, Cell cycle.

[3]  Janet Rossant,et al.  Interaction between Oct3/4 and Cdx2 Determines Trophectoderm Differentiation , 2005, Cell.

[4]  J. Rossant,et al.  Genetic regulation of stem cell origins in the mouse embryo , 2005, Clinical genetics.

[5]  K. Kroll,et al.  Geminin regulates neuronal differentiation by antagonizing Brg1 activity. , 2005, Genes & development.

[6]  Janet Rossant,et al.  Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst , 2005, Development.

[7]  Doree Sitkoff,et al.  models homology modeling : From sequence alignments to structural A comparative study of available software for high-accuracy , 2005 .

[8]  Michael A. Gonzalez,et al.  Geminin predicts adverse clinical outcome in breast cancer by reflecting cell‐cycle progression , 2004, The Journal of pathology.

[9]  Anindya Dutta,et al.  Rereplication by Depletion of Geminin Is Seen Regardless of p53 Status and Activates a G2/M Checkpoint , 2004, Molecular and Cellular Biology.

[10]  Wolfgang Wurst,et al.  A public gene trap resource for mouse functional genomics , 2004, Nature Genetics.

[11]  J. Bartek,et al.  Loss of Geminin induces rereplication in the presence of functional p53 , 2004, The Journal of cell biology.

[12]  Janet Rossant,et al.  Cdx2 is essential for axial elongation in mouse development. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Hannele Ruohola-Baker,et al.  Notch-Dependent Fizzy-Related/Hec1/Cdh1 Expression Is Required for the Mitotic-to-Endocycle Transition in Drosophila Follicle Cells , 2004, Current Biology.

[14]  Filippo Del Bene,et al.  Direct interaction of geminin and Six3 in eye development , 2004, Nature.

[15]  M. Kessel,et al.  The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions , 2004, Nature.

[16]  Z. Werb,et al.  Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells , 2003, The EMBO journal.

[17]  E. Fedorova,et al.  Endoreduplication Mediated by the Anaphase-Promoting Complex Activator CCS52A Is Required for Symbiotic Cell Differentiation in Medicago truncatula Nodules Article, publication date, and citation information can be found at www.plantcell.org/cgi/doi/10.1105/tpc.014373. , 2003, The Plant Cell Online.

[18]  Yan Geng,et al.  Cyclin E Ablation in the Mouse , 2003, Cell.

[19]  P. Abad,et al.  The Medicago Species A2-Type Cyclin Is Auxin Regulated and Involved in Meristem Formation But Dispensable for Endoreduplication-Associated Developmental Programs1 , 2003, Plant Physiology.

[20]  P. Abad,et al.  The Medicago Species A 2-Type Cyclin Is Auxin Regulated and Involved in Meristem Formation But Dispensable for Endoreduplication-Associated Developmental Programs 1 , 2003 .

[21]  Duncan Walker,et al.  Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities , 2002, Oncogene.

[22]  D. Lane,et al.  Cell type-specific responses of human cells to inhibition of replication licensing , 2002, Oncogene.

[23]  J A Wohlschlegel,et al.  Inhibition of eukaryotic DNA replication by geminin binding to Cdt1. , 2000, Science.

[24]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[25]  N. Hattori,et al.  Periodic expression of the cyclin-dependent kinase inhibitor p57(Kip2) in trophoblast giant cells defines a G2-like gap phase of the endocycle. , 2000, Molecular biology of the cell.

[26]  S. Harrison,et al.  Inhibition of Eukaryotic DNA Replication by Geminin Binding to Cdt1 , 2000 .

[27]  J. Rossant,et al.  Promotion of trophoblast stem cell proliferation by FGF4. , 1998, Science.

[28]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[29]  M. Kirschner,et al.  Geminin, an Inhibitor of DNA Replication, Is Degraded during Mitosis , 1998, Cell.

[30]  H. Schöler,et al.  Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. , 1994, Developmental biology.

[31]  P. Brûlet,et al.  Monoclonal antibodies against trophectoderm-specific markers during mouse blastocyst formation. , 1980, Proceedings of the National Academy of Sciences of the United States of America.