Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK

Abstract

Intrinsic apoptosis, reliant on BAX and BAK, has been postulated to be fundamental for morphogenesis, but its precise contribution to this process has not been fully explored in mammals. Our structural analysis of BOK suggests close resemblance to BAX and BAK structures. Notably, Bok^-/-Bax^-/-Bak^-/- animals exhibited more severe defects and died earlier than Bax^-/-Bak^-/- mice, implying that BOK has overlapping roles with BAX and BAK during developmental cell death. By analyzing Bok^-/-Bax^-/-Bak^-/- triple-knockout mice whose cells are incapable of undergoing intrinsic apoptosis, we identified tissues that formed well without this process. We provide evidence that necroptosis, pyroptosis, or autophagy does not substantially substitute for the loss of apoptosis. Albeit very rare, unexpected attainment of adult Bok^-/-Bax^-/-Bak^-/- mice suggests that morphogenesis can proceed entirely without apoptosis mediated by these proteins and possibly without cell death in general.

Keywords: BCL-2 proteins; BOK; aortic arch defects; cleft palate; exencephaly; facial cleft; midline defects; ompalocele; programmed cell death; spina bifida.