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.
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.
Cell Rep. 2018 Sep 18;24(12):3285-3295.e4. doi: 10.1016/j.celrep.2018.08.048.
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.
细胞凋亡性细胞死亡可清除不需要的细胞，并且受到 BCL-2 蛋白家族中存活促进因子和促凋亡成员之间相互作用的调控。凋亡的调控被认为对正常胚胎发育至关重要。因此，完全丧失生存促进因子 MCL-1 或 BCL-XL（BCL2L1）会导致胚胎致死。但是，尚不清楚生存促进蛋白的微小减少是否会引起发育异常。我们探讨了 MCL-1 和 BCL-XL 在发育中的限速作用，并表明 Mcl-1 和 Bcl-x 的单个等位基因的缺失的组合会导致新生儿致死。Mcl-1；Bcl-x 小鼠表现出颅面异常，但是促凋亡 Bim（Bcl2l11）的单个等位基因的进一步缺失恢复了正常发育。这些发现表明胚胎发生期间细胞存活的控制是精细平衡的，并表明一些目前未知原因的人类颅面缺陷可能是由于生存促进因子和促凋亡 BCL-2 家族成员之间的细微失衡所致。
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