Journal article
Fidgetin impacts axonal growth and branching in a local mTOR signal dependent manner
Experimental neurology, 114315
28 Dec 2022
PMID: 36586551
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
•Depletion of fidgetin resulted in increases of axon length and branching via p-mTOR/p-S6K pathway activation.•Neuronal depletion of fidgetin promoted axon sprouting and regeneration after rat spinal cord hemisection, and mTOR pathway involved in this process.•Depletion of fidgetin led to local mTOR activation in axon extension and branching of E18 cortical neurons.•Fidgetin knockdown together with a mTOR agonist L-leucine treatment synergistically augmented axonal regeneration.
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Details
- Title
- Fidgetin impacts axonal growth and branching in a local mTOR signal dependent manner
- Creators
- Chao Ma - Nantong UniversityJunpei Wang - Nantong UniversityQifeng Tu - Nantong UniversityRonghua Wu - Nantong UniversityXiaona Lai - Nantong UniversityGe Lin - Nantong UniversityZhangji Dong - Nantong UniversityTuchen Guan - Nantong UniversityLiang Qiang - Drexel UniversityYan Liu - Nantong UniversityMei Liu - Nantong University
- Publication Details
- Experimental neurology, 114315
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000973024000001
- Scopus ID
- 2-s2.0-85146093766
- Other Identifier
- 991019519009004721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences