PKC gamma promotes axonal remodeling in the cortico-spinal tract via GSK3 beta/beta-catenin signaling after traumatic brain injury
PKC gamma promotes axonal remodeling in the cortico-spinal tract via GSK3 beta/beta-catenin signaling after traumatic brain injury
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创伤性脑损伤后 PKCgamma 通过 GSK3beta/beta-catenin 信号传导促进皮质脊髓束的轴突重塑
DOI：
10.1038/s41598-019-53225-y
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发表时间：
2019
影响因子：
4.6
通讯作者：
Zou Jian
中科院分区：
文献类型：
--
作者：
Zhang Bo;Li Zaiwang;Zhang Rui;Hu Yaling;Jiang Yingdi;Cao Tingting;Wang Jingjing;Gong Lingli;Ji Li;Mu Huijun;Yang Xusheng;Dai Youai;Jiang Cheng;Yin Ying;Zou Jian
创伤性脑损伤（TBI）是导致死亡和残疾的常见原因。加强对侧皮质脊髓束（CST）向失神经侧脊髓的中线穿越有利于TBI后脊髓功能的恢复。对侧CST中PKC γ亚型的激活可能参与了创伤后CST的重塑。在本研究中，我们在体外N2 a细胞和原代皮层神经元中部署了功能丧失和获得策略，并证明PKCγ不仅是重要的，而且是神经元分化、轴突生长和轴突分支所必需的，而不是轴突延伸。在机制上，PKCγ通过磷酸化GSK 3 β，稳定胞浆β-catenin的表达，增加GAP 43的表达，从而促进轴突生长。此外，rAAV 2/9介导的在体内单侧TBI后皮质脊髓束中的组成型PKCγ的递送另外显示，将活性PKCγ突变体特异性递送至皮质神经元促进皮质脊髓纤维从未损伤侧至失神经支配的颈脊髓的中线交叉。这种PKCγ介导的损伤反应促进感觉运动功能的恢复。结论：PKCγ通过磷酸化GSK 3 β调节β-catenin的稳定性，促进神经元分化、轴突生长和轴突分支，PKCγ可能成为TBI后生理和功能恢复的新靶点。
Traumatic brain injury (TBI) is a common cause of death and disability. Enhancing the midline-crossing of the contralateral corticospinal tract (CST) to the denervated side of spinal cord facilitates functional recovery after TBI. Activation of the gamma isoform of PKC (PKCγ) in contralateral CST implicates its roles in promoting CST remodeling after TBI. In this study, we deployed loss and gain of function strategies in N2a cells and primary cortical neuronsin vitro, and demonstrated that PKCγ is not only important but necessary for neuronal differentiation, neurite outgrowth and axonal branching but not for axonal extension. Mechanically, through the phosphorylation of GSK3β, PKCγ stabilizes the expression of cytosolic β-catenin and increase GAP43 expression, thus promoting axonal outgrowth. Further, rAAV2/9-mediated delivery of constitutive PKCγ in the corticospinal tract after unilateral TBIin vivoadditionally showed that specifically delivery of active PKCγ mutant to cortical neuron promotes midline crossing of corticospinal fibers from the uninjured side to the denervated cervical spinal cord. This PKCγ-mediated injury response promoted sensorimotor functional recovery. In conclusion, PKCγ mediates stability of β-catenin through the phosphorylation of GSK3β to facilitate neuronal differentiation, neurite outgrowth and axonal branching, and PKCγ maybe a novel therapeutic target for physiological and functional recovery after TBI.