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 includ...

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Bibliographic Details
Published in:Cell 1998-09, Vol.94 (6), p.727-737
Main Authors: Cecconi, Francesco, Alvarez-Bolado, Gonzalo, Meyer, Barbara I, Roth, Kevin A, Gruss, Peter
Format: Article
Language:English
Subjects:
Alleles
Animals
Apoptosis - genetics
Apoptotic Protease-Activating Factor 1
Brain - enzymology
Brain - pathology
Caspase 3
Caspases
Chimera
Cloning, Molecular
Craniofacial Abnormalities - genetics
Cysteine Endopeptidases - metabolism
Embryo, Mammalian - abnormalities
Enzyme Activation - physiology
Eye Abnormalities
Fibroblasts - enzymology
Gene Expression Regulation, Developmental
Humans
Hyperplasia
Mammals
Mice
Molecular Sequence Data
Neurons - chemistry
Neurons - enzymology
Noonan Syndrome - genetics
Proteins - genetics
Sequence Analysis, DNA
Sequence Homology, Amino Acid
Skin Abnormalities
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Summary: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.
ISSN:0092-8674
1097-4172
DOI:10.1016/S0092-8674(00)81732-8