Geminin is essential for the development of preimplantation mouse embryos.
Replication of DNA is strictly controlled to ensure that it occurs only once per cell cycle. Geminin has been thought to serve as a central mediator of this licensing mechanism by binding to and antagonizing the function of Cdt1 and thereby preventing re-replication during S and G2 phases. We have now generated mice deficient in geminin to elucidate the physiologic role of this protein during development. Lack of geminin was shown to result in preimplantation mortality. A delay in the development of homozygous mutant embryos was first apparent at the transition from the four- to eight-cell stages, concomitant with the disappearance of maternal geminin protein, and development was arrested at the eight-cell stage. The mutant embryos manifest morphological abnormalities such as dispersed blastomeres with nuclei that are irregular both in size and shape as well as impaired cell-cell adhesion. DNA replication occurs but mitosis was not detected in the mutant embryos. The abnormal blastomeres contain damaged DNA and undergo apoptosis, likely as a consequence of the deregulation of DNA replication. Our results suggest that geminin is essential for cooperative progression of the cell cycle through S phase to M phase during the preimplantation stage of mouse development.
Hara
Kentaro
K
Department of Developmental Genetics, Center for Translational and Advanced Animal Research, Graduate School of Medicine, Tohoku University, 2-1 Seiryo, Sendai 980-8575, Japan.
Nakayama
Keiichi I
KI
Nakayama
Keiko
K
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002448:Cell Adhesion; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002970:Cleavage Stage, Ovum / Q000166:cytology / Q000378:metabolism; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004261:DNA Replication; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D064248:Geminin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008938:Mitosis; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy
D018797:Cell Cycle Proteins; D017931:DNA Primers; D064248:Geminin; C577997:Gmnn protein, mouse; D009687:Nuclear Proteins