Analysis Tools
mortality/aging
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• failure of DNA repair triggers massive female germ cell autophagy causing premature depletion of the ovarian reserve
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• although mice are born alive at the expected Mendelian ratio, only 37%, 18%, and 6% of born mice reach P7, P14, and P21, respectively
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reproductive system
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• a sharp decline in female germ cell number is first observed by P0, when ~40% of germ cells in the ovary are lost
• at P7, only rare germ cells remain, mostly localized in the cortical region of the ovary
• oocyte loss occurs primarily via autophagy, initially activated around P0 (as shown by upregulation of autophagic factors) and becoming severe at P7
• however, germ cell numbers are normal at 13.5, 15.5, 17.5 dpc
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• by P7, virtually all oocytes are undergoing autophagic degeneration
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• at P7, an increased but still limited number of TUNEL-positive germ cells are found in the ovaries
• however, percentage of TUNEL-positive germ cells in the ovaries is normal from 13.5 dpc to P0
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• at P0 and increasingly at P7, ovaries exhibit signs of fibrosis as germ cells are replaced by thick sheets of collagen; extracellular matrix proteins fill the space previously occupied by follicles
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• failure of DNA repair triggers massive female germ cell autophagy causing premature depletion of the ovarian reserve
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cellular
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• a sharp decline in female germ cell number is first observed by P0, when ~40% of germ cells in the ovary are lost
• at P7, only rare germ cells remain, mostly localized in the cortical region of the ovary
• oocyte loss occurs primarily via autophagy, initially activated around P0 (as shown by upregulation of autophagic factors) and becoming severe at P7
• however, germ cell numbers are normal at 13.5, 15.5, 17.5 dpc
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• by P7, virtually all oocytes are undergoing autophagic degeneration
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• increased autophagy involving mitochondria is observed
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• at P2, some oocytes stain positive for autophagic markers ATG7, BECN1, and LC3B, indicating signs of autophagy activation
• at P7, virtually all remaining germ cells stain positive for autophagy markers ATG7 and BECN1
• an increased conversion of LC3B from the soluble form (LC3B-I) into the membrane-bound form (LC3B-II) is seen in P7 ovaries, consistent with increased autophagy and formation of autophagosomes
• EM of P7 oocytes showed varying degrees of autophagy, ranging from a few autophagic vacuoles to cytoplasm completely filled with autolysosomes but no signs of apoptosis
• a few autophagic oocytes are first observed at 17.5 dpc
• no signs of autophagy are seen in somatic cells of the ovary
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• at P7, an increased but still limited number of TUNEL-positive germ cells are found in the ovaries
• however, percentage of TUNEL-positive germ cells in the ovaries is normal from 13.5 dpc to P0
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• oocytes fail to repair DNA damage which normally occurs when meiosis is initiated during embryonic development, and DNA damage repair genes are downregulated throughout the oocyte short lifespan
• at 17.5 dpc, but not at 13.5 or 15.5 dpc, ovaries show a severe reduction in phospho-gamma H2A.X positivity, consistent with reduced or defective DNA damage recognition and repair
• despite normal progression of meiosis, CHEK1 protein expression is downregulated at 13.5, 15.5, and 17.5 dpc
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homeostasis/metabolism
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• increased autophagy involving mitochondria is observed
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• at P2, some oocytes stain positive for autophagic markers ATG7, BECN1, and LC3B, indicating signs of autophagy activation
• at P7, virtually all remaining germ cells stain positive for autophagy markers ATG7 and BECN1
• an increased conversion of LC3B from the soluble form (LC3B-I) into the membrane-bound form (LC3B-II) is seen in P7 ovaries, consistent with increased autophagy and formation of autophagosomes
• EM of P7 oocytes showed varying degrees of autophagy, ranging from a few autophagic vacuoles to cytoplasm completely filled with autolysosomes but no signs of apoptosis
• a few autophagic oocytes are first observed at 17.5 dpc
• no signs of autophagy are seen in somatic cells of the ovary
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• oocytes fail to repair DNA damage which normally occurs when meiosis is initiated during embryonic development, and DNA damage repair genes are downregulated throughout the oocyte short lifespan
• at 17.5 dpc, but not at 13.5 or 15.5 dpc, ovaries show a severe reduction in phospho-gamma H2A.X positivity, consistent with reduced or defective DNA damage recognition and repair
• despite normal progression of meiosis, CHEK1 protein expression is downregulated at 13.5, 15.5, and 17.5 dpc
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endocrine/exocrine glands
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• at P7, an increased but still limited number of TUNEL-positive germ cells are found in the ovaries
• however, percentage of TUNEL-positive germ cells in the ovaries is normal from 13.5 dpc to P0
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• at P0 and increasingly at P7, ovaries exhibit signs of fibrosis as germ cells are replaced by thick sheets of collagen; extracellular matrix proteins fill the space previously occupied by follicles
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• failure of DNA repair triggers massive female germ cell autophagy causing premature depletion of the ovarian reserve
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