mortality/aging
• homozygotes exhibit perinatal lethality, with no mutants identified at P1
|
growth/size/body
• significantly reduced body weight at P0
|
• significantly reduced body weight at E18.5
|
• at E12.5, E14.5, and E18.5, homozygotes display significantly decreased intrauterine growth relative to controls
• however, no gross anatomical abnormalities are detected at E14.5
|
respiratory system
atelectasis
(
J:218150
)
• whereas control lungs float in water, lungs dissected from mutant newborns are dense and sink
• H&E staining revealed that the alveolar space is markedly reduced at E18.5 and P0
|
• homozygotes die soon after birth as a result of respiratory failure
|
cellular
aneuploidy
(
J:218150
)
• failure to complete cytokinesis ultimately causes aneuploidy
|
• mutant MEFs display mitotic defects and downregulation of mitotic regulators
• mitotic defects include cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation
|
• 18 of 53 mutant MEFs fail to complete cytokinesis and result in binucleated cells
|
• MEFs isolated from mid-gestation (13.5 dpc) mutant embryos exhibit reduced growth rates at passages 4 and 7 relative to wild-type MEFs
• mutant MEFs show reduced population-doubling time relative to wild-type MEFs
• reduced growth rate leads to senescence caused by mitotic defects
• decreased cell growth is not due to increased apoptosis, as shown by annexin-V staining
|
• mutant MEFs exhibit enlarged and flattened cell morphology, indicative of senescence
|
• mutant MEFs fail to maintain genomic stability, followed by abnormal chromosome segregation and cytokinesis failure
|