APAF1 IS REQUIRED FOR MITOCHONDRIAL PATHWAYS OF APOPTOSIS AND BRAIN-DEVELOPMENT

Apoptosis is essential for the precise regulation of cellular homeosta sis 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 stri king craniofacial abnormalities with hyperproliferation of neuronal ce lls. Apaf1-deficient cells were resistant to a variety of apoptotic st imuli, and the processing of Caspases 2, 3, and 8 was impaired. Howeve r, both Apaf1(-/-) thymocytes and activated T lymphocytes were sensiti ve to Fas-induced killing, showing that Fas-mediated apoptosis in thes e cells is independent of Apaf1. These data indicate that Apaf1 plays a central role in the common events of mitochondria-dependent apoptosi s in most death pathways and that this role is critical for normal dev elopment.