Vof16‐miR‐185‐5p‐GAP43 network improves the outcomes following spinal cord injury via enhancing self‐repair and promoting axonal growth

Introduction Self‐repair of spinal cord injury (SCI) has been found in humans and experimental animals with partial recovery of neurological functions. However, the regulatory mechanisms underlying the spontaneous locomotion recovery after SCI are elusive. Aims This study was aimed at evaluating the...

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Published in:CNS neuroscience & therapeutics 2024-04, Vol.30 (4), p.e14535-n/a
Main Authors: Hu, Yue, Sun, Yi‐Fei, Yuan, Hao, Liu, Jia, Chen, Li, Liu, Dong‐Hui, Xu, Yang, Zhou, Xin‐Fu, Ding, Li, Zhang, Ze‐Tao, Xiong, Liu‐Lin, Xue, Lu‐Lu, Wang, Ting‐Hua
Format: Article
Language:English
Subjects:
Animals
Body temperature
Females
GAP-43 Protein - genetics
GAP-43 Protein - metabolism
GAP43
Gene expression
Hybridization
Immunofluorescence
Laboratory animals
lncRNA volf16
Locomotion
Luciferases - metabolism
Medical research
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
miR‐185‐5p
Nervous system
neurite growth
Non-coding RNA
Original
Proteins
Rats
RNA, Long Noncoding - metabolism
self‐repair
Spinal Cord - metabolism
Spinal cord injuries
Spinal Cord Injuries - pathology
spinal cord transection
Spontaneous recovery
Surgery
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Summary:Introduction Self‐repair of spinal cord injury (SCI) has been found in humans and experimental animals with partial recovery of neurological functions. However, the regulatory mechanisms underlying the spontaneous locomotion recovery after SCI are elusive. Aims This study was aimed at evaluating the pathological changes in injured spinal cord and exploring the possible mechanism related to the spontaneous recovery. Results Immunofluorescence staining was performed to detect GAP43 expression in lesion site after spinal cord transection (SCT) in rats. Then RNA sequencing and gene ontology (GO) analysis were employed to predict lncRNA that correlates with GAP43. LncRNA smart‐silencing was applied to verify the function of lncRNA vof16 in vitro, and knockout rats were used to evaluate its role in neurobehavioral functions after SCT. MicroRNA sequencing, target scan, and RNA22 prediction were performed to further explore the underlying regulatory mechanisms, and miR‐185‐5p stands out. A miR‐185‐5p site‐regulated relationship with GAP43 and vof16 was determined by luciferase activity analysis. GAP43‐silencing, miR‐185‐5p‐mimic/inhibitor, and miR‐185‐5p knockout rats were also applied to elucidate their effects on spinal cord neurite growth and neurobehavioral function after SCT. We found that a time‐dependent increase of GAP43 corresponded with the limited neurological recovery in rats with SCT. CRNA chip and GO analysis revealed lncRNA vof16 was the most functional in targeting GAP43 in SCT rats. Additionally, silencing vof16 suppressed neurite growth and attenuated the motor dysfunction in SCT rats. Luciferase reporter assay showed that miR‐185‐5p competitively bound the same regulatory region of vof16 and GAP43. Conclusions Our data indicated miR‐185‐5p could be a detrimental factor in SCT, and vof16 may function as a ceRNA by competitively binding miR‐185‐5p to modulate GAP43 in the process of self‐recovery after SCT. Our study revealed a novel vof16‐miR‐185‐5p‐GAP43 regulatory network in neurological self‐repair after SCT and may underlie the potential treatment target for SCI. Here, we found that vof16‐miR185‐5p‐GAP43 network is closely related to SCT self‐repair, and simultaneously enhances motor and sensory function after SCT. Knocking out vof16 or GAP43 could inhibit the self‐repair of spinal cord and neurite growth, while miR‐185‐5p knockout promoted the axonal growth after SCT. Furthermore, miR‐185‐5p can competitively bind the same regulatory region
ISSN:1755-5930
1755-5949
DOI:10.1111/cns.14535