title: Caspase-12 compensates for lack of caspase-2 and caspase-3 in female germ cells.
abstract: Previously, we analyzed mice lacking either caspase-2 or caspase-3 and documented a role for caspase-2 in developmental and chemotherapy-induced apoptosis of oocytes. Those data also revealed dispensability of caspase-3, although we found this caspase critical for ovarian granulosa cell death. Because of the mutual interdependence of germ cells and granulosa cells, herein we generated caspase-2 and -3 double-mutant (DKO) mice to evaluate how these two caspases functionally relate to each other in orchestrating oocyte apoptosis. No difference was observed in the rate of spontaneous oocyte apoptosis between DKO and wildtype (WT) females. In contrast, the oocytes from DKO females were more susceptible to apoptosis induced by DNA damaging agents, compared with oocytes from WT females. This increased sensitivity to death of DKO oocytes appears to be a specific response to DNA damage, and it was associated with a compensatory upregulation of caspase-12. Interestingly, DKO oocytes were more resistant to apoptosis induced by methotrexate (MTX) than WT oocytes. These results revealed that in female germ cells, insults that directly interfere with their metabolic status (e.g. MTX) require caspase-2 and caspase-3 as obligatory executioners of the ensuing cell death cascade. However, when DNA damage is involved, and in the absence of caspase-2 and -3, caspase-12 becomes upregulated and mediates apoptosis in oocytes.
authors.affiliation: Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Takai
authors.forename: T
authors.initials: T
authors.lastname: Matikainen
authors.forename: A
authors.initials: A
authors.lastname: Jurisicova
authors.forename: M R
authors.initials: MR
authors.lastname: Kim
authors.forename: A M
authors.initials: AM
authors.lastname: Trbovich
authors.forename: E
authors.initials: E
authors.lastname: Fujita
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: B
authors.initials: B
authors.lastname: Lemmers
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: R
authors.initials: R
authors.lastname: Hakem
authors.forename: T
authors.initials: T
authors.lastname: Momoi
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: J L
authors.initials: JL
authors.lastname: Tilly
authors.forename: G I
authors.initials: GI
authors.lastname: Perez
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology*; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D048430:Cell Shape; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism; D005260:Female; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009865:Oocytes / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D010641:Phenotype; D011480:Protease Inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
chemical_list: D000903:Antibiotics, Antineoplastic; D011480:Protease Inhibitors; D004317:Doxorubicin; C506440:Casp12 protein, mouse; C090208:Casp2 protein, mouse; D053454:Caspase 12; D053143:Caspase 2; D053148:Caspase 3; D003546:Cysteine Endopeptidases