Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of integrated traditional and western medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.
J Cell Mol Med. 2018 Jan;22(1):374-381. doi: 10.1111/jcmm.13324. Epub 2017 Aug 31.
The cAMP response element-binding (CREB) protein is a member of the CREB/activating transcription factor family that is activated by various extracellular stimuli. It has been shown that CREB-dependent transcription stimulation plays a key role in neuronal differentiation and plasticity, but the underlying mechanisms remain largely elusive. Here, we show that Yes-associated protein (YAP) is a direct target induced by CREB upon retinoic acid (RA)-induced neurite outgrowth stimuli in N2a cells. Interestingly, YAP knockout using the CRISPR/Cas9 system inhibits neuronal differentiation and reduced neurite length. We further show that YAP could directly bind to CREB via its N-terminal region, and loss of YAP results in instability of phosphorylated CREB upon neurite outgrowth stimuli. Transient expression of YAP could largely restore CREB expression and neurite outgrowth in YAP knockout cells. Together, our results suggest that CREB and YAP form a positive feedback loop that is critical to maintain the stability of phosphorylated CREB and promote neurite outgrowth.
cAMP 反应元件结合蛋白（CREB）是 CREB/激活转录因子家族的成员，可被各种细胞外刺激激活。已经表明，CREB 依赖性转录刺激在神经元分化和可塑性中发挥关键作用，但潜在机制在很大程度上仍难以捉摸。在这里，我们表明 Yes 相关蛋白（YAP）是在 N2a 细胞中视黄酸（RA）诱导的神经突生长刺激下，由 CREB 诱导的直接靶标。有趣的是，使用 CRISPR/Cas9 系统敲除 YAP 会抑制神经元分化并减少神经突长度。我们进一步表明，YAP 可以通过其 N 端区域直接与 CREB 结合，并且在神经突生长刺激下，YAP 的缺失导致磷酸化 CREB 的不稳定性。YAP 的瞬时表达可以在很大程度上恢复 YAP 敲除细胞中的 CREB 表达和神经突生长。总之，我们的结果表明，CREB 和 YAP 形成正反馈回路，对于维持磷酸化 CREB 的稳定性和促进神经突生长至关重要。
