Apoptosis is a fundamental process of all mammalian cells but exactly how it is regulated in different primary cells remains less explored. In most contexts, apoptosis is engaged to eliminate cells. However, postmitotic cells such as neurons must efficiently balance the need for developmental apoptosis versus the physiological needs for their long-term survival. Neurons are capable of reversing the commitment to death even after the point of cytochrome c release. This ability of neurons to recover from an apoptotic signal suggests that activation of the apoptotic pathway in neurons could be much more transient than is currently recognized. Here, we investigated whether the apoptotic pathway in neurons is a persistent signal or a transient pulse in continuous presence of apoptotic stimulus. We have examined this at three key steps in apoptotic signaling: phosphorylation of c-Jun, induction of the BH3-only family proteins and Bax activation. Strikingly, we found all three of these events occur as transient signals following Nerve Growth Factor (NGF) deprivation-induced apoptosis in sympathetic neurons. This transient apoptosis signal would effectively allow neurons to reset and permit recovery if the apoptotic stimulus is reversed. Excitingly, we have also discovered that a neuron’s ability to recover from an apoptotic signal is dependent on expression of the anti-apoptotic Bcl-2 family protein Bcl-xL. Bcl-xL-deficient neurons lose the ability to recover from NGF deprivation even if NGF is restored. Additionally, we show that recovery from a previous exposure to NGF deprivation is protective against subsequent deprivation. Together, these results define a novel mechanism by which apoptosis is regulated in neurons where the transient pulse of the apoptotic signaling supports neuronal resilience.

细胞凋亡是所有哺乳动物细胞的基本过程，但它在不同原代细胞中的确切调节方式仍未得到充分探索。在大多数情况下，细胞凋亡是为了消除细胞。然而，神经元等有丝分裂后细胞必须有效地平衡发育性细胞凋亡的需求与其长期生存的生理需求。即使在细胞色素 c 释放之后，神经元也能够逆转对死亡的承诺。神经元从凋亡信号中恢复的这种能力表明，神经元中凋亡通路的激活可能比目前认识到的要短暂得多。在这里，我们研究了神经元中的凋亡通路是持续信号还是持续存在凋亡刺激下的瞬态脉冲。我们在凋亡信号转导的三个关键步骤中对此进行了检查：c-Jun 磷酸化、仅 BH3 家族蛋白的诱导和 Bax 激活。引人注目的是，我们发现所有这三个事件都是神经生长因子 （NGF） 剥夺诱导的交感神经元凋亡后的瞬态信号。如果凋亡刺激被逆转，这种瞬时细胞凋亡信号将有效地允许神经元重置并允许恢复。令人兴奋的是，我们还发现神经元从凋亡信号中恢复的能力取决于抗凋亡 Bcl-2 家族蛋白 Bcl-xL 的表达。即使 NGF 恢复，Bcl-xL 缺陷神经元也失去了从 NGF 剥夺中恢复的能力。此外，我们表明，从先前暴露于 NGF 剥夺中恢复对随后的剥夺具有保护作用。 总之，这些结果定义了一种新的机制，通过该机制，细胞凋亡在神经元中受到调节，其中凋亡信号转导的瞬时脉冲支持神经元弹性。