Analysis Tools
mortality/aging
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• heterozygous matings yield homozygotes at a significantly lower Mendelian ratio (15.873% versus expected 25%)
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• careful analysis of offspring generated from inbreeding with homozygotes indicates no lethality at E7.75 or E8.5, suggesting the embryonic lethality may occur at the later stage of cardiac development
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cardiovascular system
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• wheat germ agglutinin (WGA) staining shows a significant increase in cardiomyocyte size at 8 weeks of age
• however, fetal cardiomyocyte size is normal at E17.5
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• at 8 weeks of age, mice exhibit myocardial hypertrophy and expansion
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• at E17.5, the thickness of the myocardium is significantly decreased relative to that in wild-type controls
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• RT-qPCR and immunostaining assays show a significant reduction in the expression level of Kdr (kinase insert domain protein receptor; aka Flk1, fetal liver kinase 1) and % of KDR/FLK1-positive cells per cross-section at E7.75
• reduced formation of cardiomyocytes suggests that decreased expression of Kdr/Flk1 at E7.75 impairs cardiomyocyte differentiation at E8.5
• H&E staining indicates reduced cardiac lineage commitment in the heart at E17.5
• however, the differentiation potential of endoderm and ectoderm lineages and expression level of vascular and hematopoietic progenitor-associated genes are normal at E7.75
• immunostaining of ACTA2/alphaSMA-positive and CDH5/VE cadherin-positive cells indicates normal embryonic heart vasculature at E17.5
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• at E8.5, the % of TNNT2 (troponin T2, cardiac, aka cTnT)-positive cells per vertical section is significantly decreased, indicating reduced cardiomyocyte formation
• decreased cardiomyocyte number may be caused by impaired cardiac mesoderm formation
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• cell counts after dissociation by collagenases indicate a significant reduction in heart cell numbers at E17.5
• however, no changes in cardiomyocyte proliferation or apoptosis are noted in the heart at E17.5, P3 or 8 weeks of age
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• at 8 weeks of age, echocardiography shows a significant reduction in ejection fraction (EF%) and fraction shortening (FS%), indicating impaired heart function
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• at 8 weeks of age, LVID (left ventricular internal diameter) and LV volume are significantly increased at both end-diastole and end-systole while ejection fraction (EF%) and fraction shortening (FS%) are significantly decreased
• however, no changes in LV mass to body weight (BW) ratio, interventricular septum (IVS) or LV posterior wall (LVPW) are noted at 8 weeks
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muscle
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• wheat germ agglutinin (WGA) staining shows a significant increase in cardiomyocyte size at 8 weeks of age
• however, fetal cardiomyocyte size is normal at E17.5
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• at 8 weeks of age, mice exhibit myocardial hypertrophy and expansion
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• at E17.5, the thickness of the myocardium is significantly decreased relative to that in wild-type controls
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• at 8 weeks of age, echocardiography shows a significant reduction in ejection fraction (EF%) and fraction shortening (FS%), indicating impaired heart function
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growth/size/body
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• at 8 weeks of age, mice exhibit myocardial hypertrophy and expansion
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