mortality/aging
• mice die at birth
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respiratory system
• at E12.5, fewer branches are observed and the distal tips of the newly formed branches appear dilated
• the number of dilated branching tips observed at E12.5 corresponds to the number of large, fluid-filled sacs seen at E15.5
• defective branching morphogenesis occurs prior to the increased cell death seen in the distal epithelium at E13.0
• at E11.75, expression of Fgf10 (a key gene involved in lung development) is already up-regulated and expanded in the mesenchyme of mutant lungs
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• at E15.5, mutant lung epithelial cells form large, fluid-filled sacs within each lobe, indicating a severe branching defect
• at E15.5, the mutant epithelium is often detached from the mesenchyme, unlike in control lungs
• at E12.25, increased epithelial cell death is ectopically observed in the secondary bronchi of mutant lungs in addition to the normal pattern of cell death seen in the trachea and primary bronchi
• at E12.5 and E12.75, intense epithelial cell death is prolonged in the mutant trachea and bronchi, unlike in control and wild type lungs
• by E13.0, aberrant cell death is observed in the entire mutant lung epithelium, including the distal branching region, but not in the mesenchyme
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• after E13.5, each mutant lung lobe is proportionally smaller than that in control lungs
• however, each lobe maintains a normal shape, indicating a normal lobation pattern
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