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

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)3285-3295
Number of pages11
JournalCell Reports
Volume24
Issue number12
DOIs
Publication statusPublished - 18 Sep 2018

Keywords

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

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