mortality/aging
• mice die shortly after birth, probably due to neonatal hypoxia caused by lung developmental defects
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respiratory system
• alveolar epithelium is thickened at P2
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small lung
(
J:288307
)
• lung size is significantly decreased at P2
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• alveolar septum is disrupted at P2
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nervous system
• the percentage of Dcx+CSFE+ cells among CFSE+ cells, representing neuronal progeny via direct neurogenic division, is decreased at E13.5
• mice show impaired neurogenesis of cortical neurons, in particular of early-born Ctip2+ deep layer neurons; the percentage of Ctip2+BrdUfull among BrdUfull cells is significantly decreased whereas the percentage of Cux1+BrdUfull or NeuN+BrdUfull among BrdUfull cells is relatively normal
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• many PH3+ mitotic cells are abnormally stacked to form clusters at the ventricular zone (VZ) region at E14.5, unlike wild-type PH3+ cells which are aligned and attached to the apical surface of the VZ
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• mice exhibit impaired neocortex development
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• the layer thickness and numbers of Ctip2+ layer V cells, but not that of Cux1+ layer II-IV cells, are mildly but significantly reduced at P0
• the layer thickness and numbers of early formed Tbr1+ layer VI cells are significantly reduced at E18.5
• however, the number of Tbr2+ intermediate progenitor (IP) cells, which give rise to superficial layer neurons, is normal at E14.5
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• mild but significant reduction in the thickness of the dorsal lateral cortex at P0
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homeostasis/metabolism
• brain slices from E12.5 mice show an increase in caspase-9 signals that might be reflective of a DNA damage response
• brain slices show a significantly higher number of gammaH2AX+ cells at E13.5 as well as increased signals of phosphorylated-Atm (pS1981) in the VZ/SVZ regions at E14.5, suggesting activation of the DNA repair pathway
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cellular
• mice show a marked reduction in the percentage of mitotic neural progenitors (NPs) that enter a new round of the cell cycle (EdU+CFSE+ cells among CFSE+ cells), most likely due to mitotic delay
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• the number of PH3+ mitotic cells is normal at E12.5 but markedly increased in the developing cortex at E14.5 and E17.5
• the percentage of ventricular zone (VZ) cells in prophase and pro-metaphase is significantly increased at E12.5, suggesting that the increase and abnormal distribution of mitotic cells might be due to cell cycle arrest
• although total number of proliferative radial glia cells (RGs) is normal at E14.5, the percentage of RGs at mitotic phase is increased, indicating a mitotic delay in RGs at the VZ
• live imaging of mitotic RGs in cultured E13.5 brain slices revealed a higher percentage of RGs with prolonged M-phase duration (>60 min/mitotic cell)
• analysis of the division angles of RGs at the VZ region demonstrated that neural progenitors (NPs) show an increase in oblique division (30-60 degrees) at the cost of near-vertical division (60-90 degrees) at E13.5
• prolonged mitosis of ventricular RGs causes a marked reduction in the production of deep layer neurons
• however, no differences in TUNEL or cleaved caspase-3 signals are noted at E12.5 or E14.5, indicating normal apoptosis
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• the percentage of PH3+BrdU+cells among BrdU+ cells (i.e. cells arrested in mitosis) is significantly increased at E12.5
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• at E13.5, many mitotic apical NPs exhibit chromatin bridges at anaphase as well as chromosome fragments derived from chromosome misalignment or mis-segregation of sister chromatids
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• the percentage of Dcx+CSFE+ cells among CFSE+ cells, representing neuronal progeny via direct neurogenic division, is decreased at E13.5
• mice show impaired neurogenesis of cortical neurons, in particular of early-born Ctip2+ deep layer neurons; the percentage of Ctip2+BrdUfull among BrdUfull cells is significantly decreased whereas the percentage of Cux1+BrdUfull or NeuN+BrdUfull among BrdUfull cells is relatively normal
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• brain slices from E12.5 mice show an increase in caspase-9 signals that might be reflective of a DNA damage response
• brain slices show a significantly higher number of gammaH2AX+ cells at E13.5 as well as increased signals of phosphorylated-Atm (pS1981) in the VZ/SVZ regions at E14.5, suggesting activation of the DNA repair pathway
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