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Cell Rep. 2018 Sep 18;24(12):3285-3295.e4. doi: 10.1016/j.celrep.2018.08.048.

Subtle Changes in the Levels of BCL-2 Proteins Cause Severe Craniofacial Abnormalities.

Author information

1
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: sgrabow@merrimack.com.
2
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia.
3
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia.
4
Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia; Department of Anatomy and Developmental Biology and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC 3800, Australia.
5
Department of Molecular Oncology, Genentech, South San Francisco, CA 94080, USA.
6
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: avoss@wehi.edu.au.
7
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3052, Australia. Electronic address: strasser@wehi.edu.au.

Abstract

Apoptotic cell death removes unwanted cells and is regulated by interactions between pro-survival and pro-apoptotic members of the BCL-2 protein family. The regulation of apoptosis is thought to be crucial for normal embryonic development. Accordingly, complete loss of pro-survival MCL-1 or BCL-XL (BCL2L1) causes embryonic lethality. However, it is not known whether minor reductions in pro-survival proteins could cause developmental abnormalities. We explored the rate-limiting roles of MCL-1 and BCL-XL in development and show that combined loss of single alleles of Mcl-1 and Bcl-x causes neonatal lethality. Mcl-1+/-;Bcl-x+/- mice display craniofacial anomalies, but additional loss of a single allele of pro-apoptotic Bim (Bcl2l11) restores normal development. These findings demonstrate that the control of cell survival during embryogenesis is finely balanced and suggest that some human craniofacial defects, for which causes are currently unknown, may be due to subtle imbalances between pro-survival and pro-apoptotic BCL-2 family members.

KEYWORDS:

BCL-XL; BCL2L1; BCL2L11; BIM; MCL-1; MCL1; apoptosis; cyclopia; embryonic development; holoprosencephaly

PMID:
30232009
DOI:
10.1016/j.celrep.2018.08.048
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