title: Caspase 9 is constitutively activated in mouse oocytes and plays a key role in oocyte elimination during meiotic prophase progression.
abstract: In many mammalian species, more than half of the initial oocyte population is eliminated by neonatal life, thus limiting the oocyte reserve for reproduction. The cause or mechanism of this major oocyte loss remains poorly understood. We examined the apoptotic pathway involved in oocyte elimination in wild-type mouse ovaries as well as in Msh5 -/- ovaries, in which all oocytes were eliminated due to a lack of double strand break repair. Immunoblot and immunofluorescence staining showed that an initiator caspase 9 and an effector caspase 7 were constitutively activated in almost all oocytes in fetal ovaries regardless of their genotypes. In caspase 9 -/- ovaries, the total number of oocytes remained high while that in wild-type ovaries steadily declined during ovarian development. Therefore, the activation of caspase 9 was required for but did not immediately lead to oocyte demise. We found that XIAP, an endogenous inhibitor of apoptosis, was also abundant in oocytes during meiotic prophase progression. On the other hand, a cleaved form of PARP1, a target of effector caspases, was localized to the nuclei of a limited number of oocytes, and the frequency of cleaved PARP1-positive oocyte nuclei increased significantly higher before all oocytes disappeared in Msh5 -/- ovaries. We conclude that the mitochondrial apoptotic pathway mediated by caspase 9 is constitutively activated in oocytes and renders the elimination of oocytes with meiotic errors, which can be captured by the cleavage of PARP1.
authors: Department of Biology, McGill University, Urology Research Laboratory, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1.
authors: Adriana C
authors: AC
authors: Ene
authors: Stephanie
authors: S
authors: Park
authors: Winfried
authors: W
authors: Edelmann
authors: Teruko
authors: T
authors: Taketo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000172:deficiency / Q000378:metabolism*; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005333:Fetus / Q000166:cytology; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D008297:Male; D049469:Meiotic Prophase I; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009865:Oocytes / Q000166:cytology* / Q000201:enzymology*; D010053:Ovary / Q000166:cytology / Q000201:enzymology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D021381:Protein Transport; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512847:Msh5 protein, mouse; D051636:X-Linked Inhibitor of Apoptosis Protein; D011065:Poly(ADP-ribose) Polymerases; C506434:Casp9 protein, mouse; D053179:Caspase 7; D053453:Caspase 9
references: Mech Dev. 2000 May;93(1-2):139-49
references: 10781947
references: Autophagy. 2008 Feb;4(2):240-2
references: 18094606
references: Reprod Biomed Online. 2005 Feb;10(2):182-91
references: 15823221
references: Hum Genet. 1988 Mar;78(3):260-6
references: 3346015
references: J Cell Biol. 1999 Jan 25;144(2):281-92
references: 9922454
references: Dev Biol. 2003 Apr 15;256(2):331-41
references: 12679106
references: Endocrinology. 1998 Mar;139(3):1321-8
references: 9492068
references: J Cell Sci. 2007 Feb 1;120(Pt 3):417-24
references: 17213335
references: Genes Dev. 1999 Mar 1;13(5):523-31
references: 10072381
references: Cell Death Differ. 2005 Sep;12(9):1205-7
references: 16094398
references: EMBO J. 1998 Apr 15;17(8):2215-23
references: 9545235
references: Nat Rev Mol Cell Biol. 2001 Nov;2(11):838-48
references: 11715050
references: Mol Cell Biol. 2005 Apr;25(8):3348-56
references: 15798218
references: Methods Mol Biol. 2012;825:173-81
references: 22144244
references: Genes Dev. 1998 May 1;12(9):1304-14
references: 9573047
references: Biol Reprod. 2001 Apr;64(4):1153-9
references: 11259262
references: Cell. 1998 Aug 7;94(3):325-37
references: 9708735
references: Chromosoma. 1983;88(5):377-85
references: 6197255
references: Endocrinology. 2001 Jun;142(6):2468-80
references: 11356696
references: J Biol Chem. 2002 Aug 16;277(33):29803-9
references: 12065594
references: Dev Biol. 1999 Sep 1;213(1):1-17
references: 10452843
references: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):737-42
references: 15640358
references: Exp Cell Res. 1961 Sep;24:495-507
references: 13871511
references: Nat Genet. 1999 Jan;21(1):123-7
references: 9916805
references: Dev Biol. 2001 Jun 15;234(2):339-51
references: 11397004
references: Cell. 1998 Aug 7;94(3):339-52
references: 9708736
references: Dev Biol. 1994 Jun;163(2):331-40
references: 8200475
references: Reproduction. 2009 Apr;137(4):709-20
references: 19176312
references: J Neurosci. 2001 Dec 15;21(24):9519-28
references: 11739563
references: Dev Biol. 2003 Jun 15;258(2):334-48
references: 12798292
references: Biol Reprod. 2008 Nov;79(5):806-14
references: 18614702
references: IUBMB Life. 2000 Aug;50(2):85-90
references: 11185963
references: J Cell Sci. 1994 Oct;107 ( Pt 10):2749-60
references: 7876343
references: Endocrinology. 1995 Aug;136(8):3665-8
references: 7628407
references: Proc R Soc Lond B Biol Sci. 1963 Oct 22;158:417-33
references: 14070052
references: Immunity. 1999 Jun;10(6):629-39
references: 10403638
references: Mol Endocrinol. 2000 Jul;14(7):1038-52
references: 10894153
references: Nat Genet. 1999 Feb;21(2):200-3
references: 9988273
references: Cytogenet Genome Res. 2004;107(3-4):256-62
references: 15467370
references: Nature. 1997 Jul 17;388(6639):300-4
references: 9230442
references: Endocr Rev. 2006 Jun;27(4):398-426
references: 16543383
references: BMC Dev Biol. 2007 Jul 24;7:87
references: 17650311
references: Mol Cell Biol. 2001 May;21(10):3604-8
references: 11313486
references: Dev Dyn. 2005 Jun;233(2):612-22
references: 15789443
references: Cell. 2000 Apr 14;101(2):211-21
references: 10786836
references: J Bioenerg Biomembr. 1999 Aug;31(4):321-6
references: 10665522