Park Han-A, Licznerski Pawel, Alavian Kambiz N, Shanabrough Marya, Jonas Elizabeth A
Section of Endocrinology, Department of Internal Medicine, Yale University , New Haven, Connecticut.
Antioxid Redox Signal. 2015 Jan 10;22(2):93-108. doi: 10.1089/ars.2013.5570.
B-cell lymphoma-extra large (Bcl-xL) protects survival in dividing cells and developing neurons, but was not known to regulate growth. Growth and synapse formation are indispensable for neuronal survival in development, inextricably linking these processes. We have previously shown that, during synaptic plasticity, Bcl-xL produces changes in synapse number, size, activity, and mitochondrial metabolism. In this study, we determine whether Bcl-xL is required for healthy neurite outgrowth and whether neurite outgrowth is necessary for survival in developing neurons in the presence or absence of stress.
Depletion of endogenous Bcl-xL impairs neurite outgrowth in hippocampal neurons followed by delayed cell death which is dependent on upregulation of death receptor 6 (DR6), a molecule that regulates axonal pruning. Under hypoxic conditions, Bcl-xL-depleted neurons demonstrate increased vulnerability to neuronal process loss and to death compared with hypoxic controls. Endogenous DR6 expression and upregulation during hypoxia are associated with worsened neurite damage; depletion of DR6 partially rescues neuronal process loss, placing DR6 downstream of the effects of Bcl-xL on neuronal process outgrowth and protection. In vivo ischemia produces early increases in DR6, suggesting a role for DR6 in brain injury.
We suggest that DR6 levels are usually suppressed by Bcl-xL; Bcl-xL depletion leads to upregulation of DR6, failure of neuronal outgrowth in nonstressed cells, and exacerbation of hypoxia-induced neuronal injury.
Bcl-xL regulates neuronal outgrowth during development and protects neurites from hypoxic insult, as opposed by DR6. Factors that enhance neurite formation may protect neurons against hypoxic injury or neurodegenerative stimuli.
B 细胞淋巴瘤-特大（Bcl-xL）可保护分裂细胞和发育中的神经元的存活，但此前并不清楚它是否调节生长。生长和突触形成对于发育中神经元的存活不可或缺，将这些过程紧密联系在一起。我们之前已经表明，在突触可塑性过程中，Bcl-xL 会引起突触数量、大小、活性和线粒体代谢的变化。在本研究中，我们确定在有或无应激的情况下，健康的神经突生长是否需要 Bcl-xL，以及神经突生长对于发育中神经元的存活是否必要。
内源性 Bcl-xL 的缺失会损害海马神经元的神经突生长，随后导致细胞死亡延迟，这依赖于死亡受体 6（DR6）的上调，DR6 是一种调节轴突修剪的分子。在缺氧条件下，与缺氧对照组相比，Bcl-xL 缺失的神经元对神经突丢失和死亡表现出更高的易感性。缺氧期间内源性 DR6 的表达和上调与神经突损伤加重相关；DR6 的缺失部分挽救了神经突丢失，表明 DR6 在 Bcl-xL 对神经突生长和保护作用的下游。体内缺血会导致 DR6 早期增加，表明 DR6 在脑损伤中起作用。
我们认为 DR6 的水平通常被 Bcl-xL 抑制；Bcl-xL 的缺失导致 DR6 上调、非应激细胞中神经元生长失败以及缺氧诱导的神经元损伤加剧。
与 DR6 的作用相反，Bcl-xL 在发育过程中调节神经元生长，并保护神经突免受缺氧损伤。增强神经突形成的因素可能保护神经元免受缺氧损伤或神经退行性刺激。
