The intrinsic (mitochondrial) apoptotic pathway is a conserved cell death program crucial for eliminating superfluous, damaged, or incorrectly specified cells, and the multi-domain pro-death BCL-2 family proteins BAX and BAK are required for its activation. In response to internal damage or developmental signals, BAX and/or BAK permeabilize the mitochondrial outer membrane, resulting in cytochrome c release and activation of effector caspases such as Caspase-3 (Casp3). While the mitochondrial apoptotic pathway plays a critical role during late embryonic development in mammals, its role during early development remains controversial. Here, we show that Bax(-/-)Bak(-/-) murine embryonic stem cells (ESCs) display defects during the exit from pluripotency, both in culture and during teratoma formation. Specifically, we find that when ESCs are stimulated to differentiate, a subpopulation fails to do so and instead upregulates FAS in a p53-dependent manner to trigger Bax/Bak-dependent apoptosis. Blocking this apoptotic pathway prevents the removal of these poorly differentiated cells, resulting in the retention of cells that have not exited pluripotency. Taken together, our results provide further evidence for heterogeneity in the potential of ESCs to successfully differentiate and reveal a novel role for apoptosis in promoting efficient ESC differentiation by culling cells that are slow to exit pluripotency.
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