Apaf1 Is Required for Mitochondrial Pathways of Apoptosis and Brain Development

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.

Mechanisms of apoptosis by c-Myc

“…Boo is an antiapoptotic protein whose interaction with Apaf-1 is displaced by the BH3-dependent proapoptotic proteins Bak and Bik. A central role of Apaf-1 in mammalian cell apoptosis and mouse development has been demonstrated and, as expected, cells lacking Apaf-1 exhibit defects in the ability to activate apoptosis by many stimuli (Cecconi et al, 1998;Yoshida et al, 1998). However, some Apaf-1-independent apoptosis induced by certain stimuli (e.g.…”

Redundant cell death mechanisms as relics and backups

“…Such mice are deficient in a main caspase activation pathway, yet show relatively minor developmental defects, mostly forebrain hyperplasia. [30][31][32][33] Thus, most of the cell death associated with normal development in wild-type mice occurs also in the mutant mice, either through alternative caspase activation or through caspase-independent nonapoptotic cell death. Indeed, in apaf1 À/À mice, interdigital cell death occurs through caspase-independent necrosis rather than through apoptosis 34 ( Figure 2).…”

Differential tissue growth and patterns of cell death in mouse limb autopod morphogenesis

“…Similarly, in the null mice for Apaf-1, an evolutionarily conserved gene that codes for a key component of the cell death executing machinery, limbs exhibit a decrease in the number of apoptotic cells in the interdigital tissue and a delay in web elimination, but some degree of digit growth is still noticeable at S11 and could give rise to individualized digits (Cecconi et al, 1998;Yoshida et al, 1998). When BrdU was used in chicks to inhibit interdigital cell death, no effects were reported in third digit growth at early stages, during the time that digits are not normally individualized (Toné et al, 1983).…”