Department of Spine Surgery, Wenzhou Medical University First Affiliated Hospital, Wenzhou, Zhejiang 325000, China.
School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
J Neurosci. 2020 Mar 25;40(13):2644-2662. doi: 10.1523/JNEUROSCI.2229-19.2020. Epub 2020 Feb 17.
Yes-associated protein (YAP) transcriptional coactivator is negatively regulated by the Hippo pathway and functions in controlling the size of multiple organs, such as liver during development. However, it is not clear whether YAP signaling participates in the process of the formation of glia scars after spinal cord injury (SCI). In this study, we found that YAP was upregulated and activated in astrocytes of C57BL/6 male mice after SCI in a Hippo pathway-dependent manner. Conditional knockout (KO) of in astrocytes significantly inhibited astrocytic proliferation, impaired the formation of glial scars, inhibited the axonal regeneration, and impaired the behavioral recovery of C57BL/6 male mice after SCI. Mechanistically, the bFGF was upregulated after SCI and induced the activation of YAP through RhoA pathways, thereby promoting the formation of glial scars. Additionally, YAP promoted bFGF-induced proliferation by negatively controlling nuclear distribution of p27 mediated by CRM1. Finally, bFGF or XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) injection indeed activated YAP signaling and promoted the formation of glial scars and the functional recovery of mice after SCI. These findings suggest that YAP promotes the formation of glial scars and neural regeneration of mice after SCI, and that the bFGF-RhoA-YAP-p27 pathway positively regulates astrocytic proliferation after SCI. Glial scars play critical roles in neuronal regeneration of CNS injury diseases, such as spinal cord injury (SCI). Here, we provide evidence for the function of Yes-associated protein (YAP) in the formation of glial scars after SCI through regulation of astrocyte proliferation. As a downstream of bFGF (which is upregulated after SCI), YAP promotes the proliferation of astrocytes through negatively controlling nuclear distribution of p27 mediated by CRM1. Activation of YAP by bFGF or XMU-MP-1 injection promotes the formation of glial scar and the functional recovery of mice after SCI. These results suggest that the bFGF-RhoA-YAP-p27 axis for the formation of glial scars may be a potential therapeutic strategy for SCI patients.
Yes 相关蛋白 (YAP) 转录共激活因子受 Hippo 通路的负调控，在控制多个器官的大小（如发育过程中的肝脏）中起作用。然而，目前尚不清楚 YAP 信号是否参与脊髓损伤 (SCI) 后神经胶质瘢痕的形成过程。在这项研究中，我们发现 YAP 在 SCI 后 C57BL/6 雄性小鼠的星形胶质细胞中呈上调和激活状态，且这种激活是依赖 Hippo 通路的。星形胶质细胞特异性敲除 (KO) 可显著抑制星形胶质细胞增殖，损伤神经胶质瘢痕形成，抑制轴突再生，损害 SCI 后 C57BL/6 雄性小鼠的行为恢复。机制上，SCI 后 bFGF 上调，并通过 RhoA 通路诱导 YAP 激活，从而促进神经胶质瘢痕的形成。此外，YAP 通过 CRM1 负调控 p27 的核分布来促进 bFGF 诱导的增殖。最后，bFGF 或 XMU-MP-1（一种抑制 Hippo 激酶 MST1/2 以激活 YAP 的抑制剂）注射确实激活了 YAP 信号，并促进了 SCI 后神经胶质瘢痕的形成和小鼠的功能恢复。这些发现表明，YAP 促进 SCI 后小鼠神经胶质瘢痕的形成和神经再生，bFGF-RhoA-YAP-p27 通路正向调节 SCI 后星形胶质细胞增殖。神经胶质瘢痕在中枢神经系统损伤疾病（如脊髓损伤 (SCI)）的神经元再生中起关键作用。在这里，我们通过调节星形胶质细胞增殖为 YAP 在 SCI 后神经胶质瘢痕形成中的功能提供了证据。作为 bFGF（SCI 后上调）的下游分子，YAP 通过 CRM1 负调控 p27 的核分布来促进星形胶质细胞的增殖。bFGF 或 XMU-MP-1 注射激活 YAP 促进了 SCI 后神经胶质瘢痕的形成和小鼠的功能恢复。这些结果表明，bFGF-RhoA-YAP-p27 轴对于神经胶质瘢痕的形成可能是 SCI 患者的一种潜在治疗策略。
