Apaf1 is required for mitochondrial pathways of apoptosis and brain development.
Apoptosis is essential for the precise regulation of cellular homeostasis and development. The role in vivo of Apaf1, a mammalian homolog of C. elegans CED-4, was investigated in gene-targeted Apaf1-/- mice. Apaf1-deficient mice exhibited reduced apoptosis in the brain and striking craniofacial abnormalities with hyperproliferation of neuronal cells. Apaf1-deficient cells were resistant to a variety of apoptotic stimuli, and the processing of Caspases 2, 3, and 8 was impaired. However, both Apaf1-/- thymocytes and activated T lymphocytes were sensitive to Fas-induced killing, showing that Fas-mediated apoptosis in these cells is independent of Apaf1. These data indicate that Apaf1 plays a central role in the common events of mitochondria-dependent apoptosis in most death pathways and that this role is critical for normal development.
Yoshida
H
H
The Amgen Institute, Department of Medical Biophysics, University of Toronto, Canada.
Kong
Y Y
YY
Yoshida
R
R
Elia
A J
AJ
Hakem
A
A
Hakem
R
R
Penninger
J M
JM
Mak
T W
TW
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D001921:Brain / Q000166:cytology* / Q000196:embryology*; D001923:Brain Chemistry / Q000502:physiology; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities; D004792:Enzyme Precursors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015870:Gene Expression; D006257:Head / Q000002:abnormalities; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012868:Skin Abnormalities; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013601:T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects; D013950:Thymus Gland / Q000737:chemistry / Q000166:cytology / Q000528:radiation effects; D014466:Ultraviolet Rays; D019014:fas Receptor / Q000502:physiology
C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D011506:Proteins; D019014:fas Receptor; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases