Some mice lacking intrinsic, as well as death receptor induced apoptosis and necroptosis, can survive to adulthood

Programmed cell death, in particular the intrinsic apoptotic pathway, has been shown to play a critical role in the shaping of tissues during embryonic development. The multi-BCL-2 Homology (BH) domain effectors of apoptosis, BAX, BAK, and BOK, are essential for cell killing in the intrinsic apoptotic pathway. It was therefore surprising that we found earlier that a few mice lacking all effectors of apoptosis (Bax;Bak;Bok triple knockout), albeit many fewer than expected based on Mendelian ratios, could reach weaning or even adulthood. This indicated that death receptor induced apoptosis or necroptosis, a lytic form of programmed cell death, may also have roles in embryogenesis alongside the intrinsic apoptotic pathway. To explore this, we generated Bax;Bak;Bok;caspase-8;Mlkl quintuple knockout mice, which lack not only intrinsic apoptosis but also death receptor induced apoptosis (loss of caspase-8) and necroptosis (loss of MLKL). These foetuses exhibited similar defects to the Bax;Bak;Bok triple knockout mice and, intriguingly, a small number of Bax;Bak;Bok;caspase-8;Mlkl quintuple knockout mice could reach weaning or even adulthood. These findings identify the contributions of these three programmed cell death pathways to embryonic development and show that despite the absence of all of them, development to adulthood is possible, albeit very rare.