1. Academic Validation
  2. Fidgetin impacts axonal growth and branching in a local mTOR signal dependent manner

Fidgetin impacts axonal growth and branching in a local mTOR signal dependent manner

  • Exp Neurol. 2022 Dec 28;114315. doi: 10.1016/j.expneurol.2022.114315.
Chao Ma 1 Junpei Wang 2 Qifeng Tu 2 Ronghua Wu 2 Xiaona Lai 2 Ge Lin 2 Zhangji Dong 2 Tuchen Guan 2 Liang Qiang 3 Yan Liu 4 Mei Liu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, China; Medical School of Nantong University, Nantong, Jiangsu 226001, China.
  • 2 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, China.
  • 3 Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, United States of America.
  • 4 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, China. Electronic address: liuyan@ntu.edu.cn.
  • 5 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, China. Electronic address: liumei@ntu.edu.cn.
Abstract

Neurons require a constant increase in protein synthesis during axonal growth and regeneration. AKT-mTOR is a central pathway for mammalian cell survival and regeneration. Fidgetin (Fign) is an ATP-dependent microtubule (MT)-severing Enzyme whose functions are associated with neurite outgrowth, axon regeneration and cell migration. Although most previous studies have indicated that depletion of Fign is involved in those biological activities by increasing labile MT mass, it remains unknown whether mTOR activation contributes to this process. Here, we showed that depletion of Fign enhanced p-mTOR/p-S6K activation, and the mTOR Inhibitor Rapamycin inhibited axon outgrowth and p-rpS6 activation. We then investigated the effects of neuronal-specific Fign deletion in a rat spinal cord hemisection model by injecting syn-GFP Fign shRNA virus. BBB values revealed an improvement in functional recovery. The p-mTOR was activated along with neuronal Fign depletion. The syn-mCherry virus showed more sprouting neurites entering the injury region, which was confirmed by immunostaining GAP43 protein. Further, we showed that Fign siRNA treatment promoted axon outgrowth and branching, whose underlying mechanism was firstly attributed to local activation of the mTOR pathway, and increased MT dynamicity. Finally, considering L-leucine, promotes axonal growth and neuronal survival, we applied L-leucine with Fign depletion after spinal cord injury or in chondroitin sulfate proteoglycan inhibitory molecules. The phenomenon of synergistically augmented axon regeneration was observed. In summary, our results indicated a novel local mTOR pathway for fidgetin to impact axon growth and provided a combined strategy in SCI.

Keywords

Axonal outgrowth; Fidgetin (Fign); L-leucine; Spinal cord injury; mTOR (mammalian target of rapamycin).

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