RT Journal Article
SR Electronic
T1 Astrocytic YAP Promotes the Formation of Glia Scars and Neural Regeneration after Spinal Cord Injury
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2644
OP 2662
DO 10.1523/JNEUROSCI.2229-19.2020
VO 40
IS 13
A1 Changnan Xie
A1 Xiya Shen
A1 Xingxing Xu
A1 Huitao Liu
A1 Fayi Li
A1 Sheng Lu
A1 Ziran Gao
A1 Jingjing Zhang
A1 Qian Wu
A1 Danlu Yang
A1 Xiaomei Bao
A1 Fan Zhang
A1 Shiyang Wu
A1 Zhaoting Lv
A1 Minyu Zhu
A1 Dingjun Xu
A1 Peng Wang
A1 Liying Cao
A1 Wei Wang
A1 Zengqiang Yuan
A1 Ying Wang
A1 Zhaoyun Li
A1 Honglin Teng
A1 Zhihui Huang
YR 2020
UL http://www.jneurosci.org/content/40/13/2644.abstract
AB 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 yap 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 p27Kip1 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-p27Kip1 pathway positively regulates astrocytic proliferation after SCI.SIGNIFICANCE STATEMENT 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 p27Kip1 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-p27Kip1 axis for the formation of glial scars may be a potential therapeutic strategy for SCI patients.