Subtle Changes in the Levels of BCL-2 Proteins Cause Severe Craniofacial Abnormalities
Stephanie Grabow,
Andrew J. Kueh,
Francine Ke,
Hannah K. Vanyai,
Bilal N. Sheikh,
Michael A. Dengler,
William Chiang,
Samantha Eccles,
Ian M. Smyth,
Lynelle K. Jones,
Frederic J. de Sauvage,
Mark Scott,
Lachlan Whitehead,
Anne K. Voss,
Andreas Strasser
Affiliations
Stephanie Grabow
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; Corresponding author
Andrew J. Kueh
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
Francine Ke
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
Hannah K. Vanyai
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
Bilal N. Sheikh
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
Michael A. Dengler
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
William Chiang
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
Samantha Eccles
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Ian M. Smyth
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
Lynelle K. Jones
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
Frederic J. de Sauvage
Department of Molecular Oncology, Genentech, South San Francisco, CA 94080, USA
Mark Scott
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia
Lachlan Whitehead
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
Anne K. Voss
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; Corresponding author
Andreas Strasser
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; Corresponding author
Summary: 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. : Grabow et al. find that combined loss of single alleles of pro-survival Mcl-1 and Bcl-x causes craniofacial defects, including holoprosencephaly, a severe birth defect. Normal development is restored by concomitant loss of a single allele of pro-apoptotic Bim, revealing that cell survival and cell death during embryogenesis are finely balanced. Keywords: MCL-1, MCL1, BCL-XL, BCL2L1, BIM, BCL2L11, apoptosis, embryonic development, holoprosencephaly, cyclopia
