Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development.
The cytosolic protein APAF1, human homolog of C. elegans CED-4, participates in the CASPASE 9 (CASP9)-dependent activation of CASP3 in the general apoptotic pathway. We have generated by gene trap a null allele of the murine Apaf1. Homozygous mutants die at embryonic day 16.5. Their phenotype includes severe craniofacial malformations, brain overgrowth, persistence of the interdigital webs, and dramatic alterations of the lens and retina. Homozygous embryonic fibroblasts exhibit reduced response to various apoptotic stimuli. In situ immunodetection shows that the absence of Apaf1 protein prevents the activation of Casp3 in vivo. In agreement with the reported function of CED-4 in C. elegans, this phenotype can be correlated with a defect of apoptosis. Our findings suggest that Apaf1 is essential for Casp3 activation in embryonic brain and is a key regulator of developmental programmed cell death in mammals.
Cecconi
F
F
Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany.
Alvarez-Bolado
G
G
Meyer
B I
BI
Roth
K A
KA
Gruss
P
P
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053477:Apoptotic Protease-Activating Factor 1; D001921:Brain / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases; D002678:Chimera; D003001:Cloning, Molecular; D019465:Craniofacial Abnormalities / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities; D004789:Enzyme Activation / Q000502:physiology; D005124:Eye Abnormalities; D005347:Fibroblasts / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D006965:Hyperplasia; D008322:Mammals; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000737:chemistry / Q000201:enzymology; D009634:Noonan Syndrome / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D012868:Skin Abnormalities
C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D011506:Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases