Murine Wee1 plays a critical role in cell cycle regulation and pre-implantation stages of embryonic development.
Wee1 kinase regulates the G2/M cell cycle checkpoint by phosphorylating and inactivating the mitotic cyclin-dependent kinase 1 (Cdk1). Loss of Wee1 in many systems, including yeast and drosophila, leads to premature mitotic entry. However, the developmental role of Wee1 in mammals remains unclear. In this study, we established Wee1 knockout mice by gene targeting. We found that Wee-/- embryos were defective in the G2/M cell cycle checkpoint induced by gamma-irradiation and died of apoptosis before embryonic (E) day 3.5. To study the function of Wee1 further, we have developed MEF cells in which Wee1 is disrupted by a tamoxifen inducible Cre-LoxP approach. We found that acute deletion of Wee1 resulted in profound growth defects and cell death. Wee1 deficient cells displayed chromosome aneuploidy and DNA damage as revealed by gamma-H2AX foci formation and Chk2 activation. Further studies revealed a conserved mechanism of Wee1 in regulating mitotic entry and the G2/M checkpoint compared with other lower organisms. These data provide in vivo evidence that mammalian Wee1 plays a critical role in maintaining genome integrity and is essential for embryonic survival at the pre-implantation stage of mouse development.
Tominaga
Yohei
Y
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10/9N105, NIH, Bethesda, MD 20892, USA.
Li
Cuiling
C
Wang
Rui-Hong
RH
Deng
Chu-Xia
CX
D000818:Animals; D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D001755:Blastocyst / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology*; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D003433:Crosses, Genetic; D005298:Fertility; D005313:Fetal Death; D016195:G2 Phase / Q000502:physiology / Q000528:radiation effects; D005720:Gamma Rays; D016678:Genome; D015698:Genomic Library; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D014886:Weaning
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse