Cell
Volume 173, Issue 5, 17 May 2018, Pages 1217-1230.e17
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Article
Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK

https://doi.org/10.1016/j.cell.2018.04.036Get rights and content
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Highlights

  • BOK, BAX, and BAK have similar structures and overlapping roles during development

  • BOK/BAX/BAK triple-null mice have more severe defects than BAX/BAK double knockouts

  • Intrinsic apoptosis is critical for midline fusion and aortic arch formation

  • A small number of BOK/BAX/BAK triple-null mice develop entirely without apoptosis

Summary

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

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

Cited by (0)

3

Present address: The Francis Crick Institute, Kings Cross, London, NW1 1AT, UK

4

Present address: Multiple Sclerosis and Neuroimmunology Research Unit, Biogen, Cambridge, MA 02142, USA

5

Present address: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA

6

These authors contributed equally

7

Senior author

8

Lead contact