Caspase-2 deficiency prevents programmed germ cell death resulting from cytokine insufficiency but not meiotic defects caused by loss of ataxia telangiectasia-mutated (Atm) gene function.
It is well established that programmed cell death claims up to two-thirds of the oocytes produced during gametogenesis in the developing fetal ovaries. However, the mechanisms underlying prenatal germ cell loss in females remain poorly understood. Herein we report that caspase-11 null female mice are born with a reduced number of oocyte-containing primordial follicles. This phenotype is likely due to failed cytokine processing known to occur in caspase-11 mutants since neonatal female mice lacking both interleukin (IL)-1alpha and IL-1beta also exhibit a reduced endowment of primordial follicles. In addition, germ cell death in wild-type fetal ovaries cultured ex vivo is suppressed by either cytokine, likely via ligand activation of type 1 IL-1 receptors expressed in fetal germ cells. Normal oocyte endowment can be restored in caspase-11 null female mice by simultaneous inactivation of the gene encoding the cell death executioner enzyme, caspase-2. However, caspase-2 deficiency cannot overcome gametogenic failure resulting from meiotic recombination defects in ataxia telangiectasia-mutated (Atm) null female mice. Thus, genetically distinct mechanisms exist for developmental deletion of oocytes via programmed cell death, one of which probably functions as a meiotic quality-control checkpoint that cannot be overridden.
Morita
Y
Y
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Maravei
D V
DV
Bergeron
L
L
Wang
S
S
Perez
G I
GI
Tsutsumi
O
O
Taketani
Y
Y
Asano
M
M
Horai
R
R
Korsmeyer
S J
SJ
Iwakura
Y
Y
Yuan
J
J
Tilly
J L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D020170:Caspase 1 / Q000378:metabolism; D053455:Caspase 10; D053143:Caspase 2; D020169:Caspases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D053471:Caspases, Initiator; D018797:Cell Cycle Proteins; D016207:Cytokines / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D004268:DNA-Binding Proteins; D005260:Female; D017353:Gene Deletion; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009865:Oocytes / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein
D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C101136:Casp4 protein, mouse; D053455:Caspase 10; D053143:Caspase 2; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1