PKC gamma promotes axonal remodeling in the cortico-spinal tract via GSK3 beta/beta-catenin signaling after traumatic brain injury

Zhang, Bo1,2; Li, Zaiwang3,4; Zhang, Rui1,5; Hu, Yaling1,2; Jiang, Yingdi1,2; Cao, Tingting4; Wang, Jingjing1,2; Gong, Lingli1,2; Ji, Li1,2; Mu, Huijun1,2; Yang, Xusheng1,2; Dai, Youai1,2; Jiang, Cheng1,2; Yin, Ying1,2; Zou, Jian1,2

2019-11-19

10.1038/s41598-019-53225-y

Scientific Reports   影响因子和分区

2045-2322

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 (PKC gamma) 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 neurons in vitro, and demonstrated that PKC gamma is not only important but necessary for neuronal differentiation, neurite outgrowth and axonal branching but not for axonal extension. Mechanically, through the phosphorylation of GSK3 beta, PKC gamma stabilizes the expression of cytosolic beta-catenin and increase GAP43 expression, thus promoting axonal outgrowth. Further, rAAV2/9-mediated delivery of constitutive PKC gamma in the corticospinal tract after unilateral TBI in vivo additionally showed that specifically delivery of active PKC gamma mutant to cortical neuron promotes midline crossing of corticospinal fibers from the uninjured side to the denervated cervical spinal cord. This PKC gamma-mediated injury response promoted sensorimotor functional recovery. In conclusion, PKC gamma mediates stability of beta-catenin through the phosphorylation of GSK3 beta to facilitate neuronal differentiation, neurite outgrowth and axonal branching, and PKC gamma maybe a novel therapeutic target for physiological and functional recovery after TBI.

SCI

英语

其他

Wuxi Commission of Health Precision Medicine Special Funds[J201803]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000497701800035

NATURE PUBLISHING GROUP

Web of Science

1.Nanjing Med Univ, Clin Res Ctr, Affiliated Wuxi Peoples Hosp, Wuxi 214023, Jiangsu, Peoples R China
2.Wuxi Inst Translat Med, Wuxi 214023, Jiangsu, Peoples R China
3.Southern Univ Sci & Technol, Affiliated Hosp So 1, Jinan Univ,Dept Neurol, Shenzhen Peoples Hosp,Clin Med Coll 2, Shenzhen 518020, Guangdong, Peoples R China
4.Nanjing Med Univ, Dept Neurol, Affiliated Wuxi Peoples Hosp, Wuxi 214023, Jiangsu, Peoples R China
5.Nanjing Med Univ, Affiliated Wuxi Peoples Hosp, Dept Neurosurg, Wuxi 214023, Jiangsu, Peoples R China

Zhang, Bo,Li, Zaiwang,Zhang, Rui,et al. PKC gamma promotes axonal remodeling in the cortico-spinal tract via GSK3 beta/beta-catenin signaling after traumatic brain injury[J]. Scientific Reports,2019,9.

Zhang, Bo.,Li, Zaiwang.,Zhang, Rui.,Hu, Yaling.,Jiang, Yingdi.,...&Zou, Jian.(2019).PKC gamma promotes axonal remodeling in the cortico-spinal tract via GSK3 beta/beta-catenin signaling after traumatic brain injury.Scientific Reports,9.

Zhang, Bo,et al."PKC gamma promotes axonal remodeling in the cortico-spinal tract via GSK3 beta/beta-catenin signaling after traumatic brain injury".Scientific Reports 9(2019).