Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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Apoptotic Protease-Activating Factor 1
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Brain / cytology*
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Brain / embryology*
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Brain Chemistry / physiology
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Caspase 2
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases*
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Cells, Cultured
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Cysteine Endopeptidases / metabolism
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Cytochrome c Group / metabolism
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Embryo, Mammalian / abnormalities
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Enzyme Precursors / metabolism
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Fibroblasts / cytology
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Fibroblasts / enzymology
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Gene Expression
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Head / abnormalities
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Membrane Potentials / physiology
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Mice
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Mice, Knockout
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Mitochondria / enzymology*
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Phenotype
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Proteins / genetics*
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Proteins / immunology
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Proteins / metabolism
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Skin Abnormalities
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Stem Cells / cytology
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Stem Cells / metabolism
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T-Lymphocytes / chemistry
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T-Lymphocytes / cytology
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T-Lymphocytes / radiation effects
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Thymus Gland / chemistry
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Thymus Gland / cytology
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Thymus Gland / radiation effects
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Ultraviolet Rays
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fas Receptor / physiology
Substances
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Apaf1 protein, mouse
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Apoptotic Protease-Activating Factor 1
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Cytochrome c Group
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Enzyme Precursors
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Proteins
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fas Receptor
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Casp3 protein, mouse
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Casp8 protein, mouse
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Casp9 protein, mouse
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Caspase 2
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases
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Cysteine Endopeptidases