The role of novel genes in axon regeneration after CNS injury– A Systematic review and Meta-analysis
Main Article Content
Keywords
CNS injury, Spinal cord injury, Axon regeneration, Neural injury, Genes, Genetic markers
Abstract
Background: Novel genes and their implications towards different facets of medicine are all the rage in today’s scientific community. This investigation was conducted to ascertain the effects of these genetic sequences on the regeneration potential of axons that were damaged due to injury to the central nervous system (CNS).
Methods: Articles relevant to our aims and objectives were scoured across different online databases from the year 2018 onwards to provide an updated view in this regard.
Results: 9 studies were selected after application of the requisite selection criterion. The studies mainly used mice as subjects, while one evaluated the effects on sea lampreys and African clawed frog species. The analysis included studies reporting the noticeable vs negligible effects of genetic sequences on axon regeneration, with an overall odds ratio (OR) of 0.52 (95% CI: 0.45, 0.60) and a statistically significant difference between the groups (Z = 8.84, P < 0.00001). A relative risk of 0.60 and a 95% confidence interval of 0.54 to 0.68 was also obtained. There was no significant heterogeneity between the studies, indicating that the effect size was consistent across the studies.
Conclusion: The results showed that different proteins were coded for different injury models, indicating that genetic sequences play a noticeable role in the ability of axons to regenerate after CNS injury. However, considering the limitations of our study, the need for more such statistical analysis using different genetic examples is warranted.
References
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2. Neumann S, and Woolf CJ (1999). Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83–91.
3. Hilton BJ, Husch A, Schaffran B, Lin TC, Burnside ER, Dupraz S, Schelski M, Kim J, Müller JA, Schoch S, et al. (2022). An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury. Neuron 110, 51–69.e7. 10.1016/j.neuron.2021.10.007.
4. Palmisano I, Danzi MC, Hutson TH, Zhou L, McLachlan E, Serger E, Shkura K, Srivastava PK, Hervera A, Neill NO, et al. (2019). Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons. Nat. Neurosci 22, 1913–1924. 10.1038/s41593-019-0490-4.
5. Weng YL, Wang X, An R, Cassin J, Vissers C, Liu Y, Liu Y, Xu T, Wang X, Wong SZH, et al. (2018). Epitranscriptomic m(6)A regulation of axon regeneration in the adult mammalian nervous system. Neuron 97, 313–325.e316. 10.1016/j.neuron.2017.12.036
6. Tedeschi A, Dupraz S, Laskowski CJ, Xue J, Ulas T, Beyer M, Schultze JL, and Bradke F (2016). The calcium channel subunit Alpha2delta2 suppresses axon regeneration in the adult CNS. Neuron 92, 419–434. 10.1016/j.neuron.2016.09.026
7. Yang C, Wang X, Wang J, Wang X, Chen W, Lu N, Siniossoglou S, Yao Z, and Liu K (2020). Rewiring neuronal glycerolipid metabolism determines the extent of axon regeneration. Neuron 105, 276–292.e5. 10.1016/j.neuron.2019.10.009
8. Mahar M, and Cavalli V (2018). Intrinsic mechanisms of neuronal axon regeneration. Nat. Rev. Neurosci 19, 323–337. 10.1038/s41583-018-0001-8
9. Fawcett JW (2020). The struggle to make CNS axons regenerate: why has it been so difficult? Neurochem. Res 45, 144–158. 10.1007/s11064-019-02844-y
10. He Z, and Jin Y (2016). Intrinsic control of axon regeneration. Neuron 90, 437–451. 10.1016/j.neuron.2016.04.022
11. Tedeschi A, and Bradke F (2017). Spatial and temporal arrangement of neuronal intrinsic and extrinsic mechanisms controlling axon regeneration. Curr. Opin. Neurobiol 42, 118–127. 10.1016/j.conb.2016.12.005
12. Silver J, Schwab ME, and Popovich PG (2014). Central nervous system regenerative failure: role of oligodendrocytes, astrocytes, and microglia. Cold Spring Harb. Perspect. Biol 7, a020602. 10.1101/cshperspect.a020602.
13. Benowitz LI, and Popovich PG (2011). Inflammation and axon regeneration. Curr. Opin. Neurol 24, 577–583. 10.1097/WCO.0b013e32834c208d
14. Hu Z, Deng N, Liu K, Zhou N, Sun Y, and Zeng W (2020). CNTF-STAT3-IL-6 axis mediates neuroinflammatory cascade across Schwann cell-neuron-microglia. Cell Rep 31, 107657. 10.1016/j.celrep.2020.107657.
15. Wang Q, Zhang S, Liu T, Wang H, Liu K, Wang Q, and Zeng W (2018). Sarm1/Myd88–5 regulates neuronal intrinsic immune response to traumatic axonal injuries. Cell Rep 23, 716–724. 10.1016/j.celrep.2018.03.071
16. Ben-Yaakov K, Dagan SY, Segal-Ruder Y, Shalem O, Vuppalanchi D, Willis DE, Yudin D, Rishal I, Rother F, Bader M, et al. (2012). Axonal transcription factors signal retrogradely in lesioned peripheral nerve. EMBO J 31, 1350–1363. 10.1038/emboj.2011.494
17. Qiu J, Cafferty WB, McMahon SB, and Thompson SW (2005). Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation. J. Neurosci 25, 1645–1653. 10.1523/JNEUROSCI.3269-04.2005.
18. Smith PD, Sun F, Park KK, Cai B, Wang C, Kuwako K, Martinez-Carrasco I, Connolly L, and He Z (2009). SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron 64, 617–623. 10.1016/j.neuron.2009.11.021
19. Sas AR, Carbajal KS, Jerome AD, Menon R, Yoon C, Kalinski AL, Giger RJ, and Segal BM (2020). A new neutrophil subset promotes CNS neuron survival and axon regeneration. Nat. Immunol 21, 1496–1505. 10.1038/s41590-020-00813-0.
20. Baldwin KT, Carbajal KS, Segal BM, and Giger RJ (2015). Neuroinflammation triggered by beta-glucan/dectin-1 signaling enables CNS axon regeneration. Proc. Natl. Acad. Sci. USA 112, 2581–2586. 10.1073/pnas.1423221112.
21. Yin Y, Cui Q, Li Y, Irwin N, Fischer D, Harvey AR, and Benowitz LI (2003). Macrophage-derived factors stimulate optic nerve regeneration. J. Neurosci 23, 2284–2293.
22. Schroder K, Hertzog PJ, Ravasi T, and Hume DA (2004). Interferongamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol 75, 163–189. 10.1189/jlb.0603252.
23. Roselli F, Chandrasekar A, and Morganti-Kossmann MC (2018). Interferons in traumatic brain and spinal cord injury: current evidence for translational application. Front. Neurol 9, 458. 10.3389/fneur.2018.00458.
24. Warre-Cornish K, Perfect L, Nagy R, Duarte RRR, Reid MJ, Raval P, Mueller A, Evans AL, Couch A, Ghevaert C, et al. (2020). Interferon-gamma signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorderphenotypes. Sci. Adv 6, eaay9506. 10.1126/sciadv.aay9506
25. Yasuda M, Nagappan-Chettiar S, Johnson-Venkatesh EM, and Umemori H (2021). An activity-dependent determinant of synapse elimination in the mammalian brain. Neuron 109, 1333–1349.e6. 10.1016/j.neuron.2021.03.006
26. Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, et al. (2016). Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature 535, 425–429. 10.1038/nature18626.
27. Ma F, Li B, Yu Y, Iyer SS, Sun M, and Cheng G (2015). Positive feedback regulation of type I interferon by the interferon-stimulated gene STING. EMBO Rep 16, 202–212. 10.15252/embr.201439366.
28. Ma F, Li B, Liu SY, Iyer SS, Yu Y, Wu A, and Cheng G (2015). Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS. J. Immunol 194, 1545–1554. 10.4049/jimmunol.1402066
29. Ablasser A, and Chen ZJ (2019). cGAS in action: expanding roles in immunity and inflammation. Science 363, eaat8657. 10.1126/science.aat8657
30. Zhang D, Liu C, Li H, and Jiao J (2020). Deficiency of STING signaling in embryonic cerebral cortex leads to neurogenic abnormalities and autistic-like behaviors. Adv. Sci. (Weinh) 7, 2002117. 10.1002/advs.202002117
31. Donnelly CR, Jiang C, Andriessen AS, Wang K, Wang Z, Ding H, Zhao J, Luo X, Lee MS, Lei YL, et al. (2021). STING controls nociception via type I interferon signalling in sensory neurons. Nature 591, 275–280. 10.1038/s41586-020-03151-1
32. Frey E, Valakh V, Karney-Grobe S, Shi Y, Milbrandt J, and DiAntonio A (2015). An in vitro assay to study induction of the regenerative state in sensory neurons. Exp. Neurol 263, 350–363. 10.1016/j.expneurol.2014.10.012
33. Saijilafu Hur, E.M., Liu, C.M., Jiao, Z., Xu, W.L., and Zhou, F.Q. (2013). PI3K-GSK3 signalling regulates mammalian axon regeneration by inducing the expression of Smad1. Nat. Commun 4, 2690. 10.1038/ncomms3690.
34. Fisher D, Xing B, Dill J, Li H, Hoang HH, Zhao Z, Yang XL, Bachoo R, Cannon S, Longo FM, et al. (2011). Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors. J. Neurosci 31, 14051–14066. 10.1523/JNEUROSCI.1737-11.2011
35. Shen Y, Tenney AP, Busch SA, Horn KP, Cuascut FX, Liu K, He Z, Silver J, and Flanagan JG (2009). PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596. 10.1126/science.1178310.
36. Park KK, Liu K, Hu Y, Smith PD, Wang C, Cai B, Xu B, Connolly L, Kramvis I, Sahin M, and He Z (2008). Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966.
37. Hooijmans, C.R., Rovers, M.M., de Vries, R.B. et al. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14, 43 (2014). https://doi.org/10.1186/1471-2288-14-43
38. Liberati, A. (2009). The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: Explanation and elaboration. Annals of Internal Medicine, 151(4), W. doi:10.7326/0003-4819-151-4-200908180-00136
39. Burnside ER, De Winter F, Didangelos A, James ND, Andreica EC, Layard-Horsfall H, Muir EM, Verhaagen J, Bradbury EJ. Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. Brain. 2018 Aug 1;141(8):2362-2381. doi: 10.1093/brain/awy158. PMID: 29912283; PMCID: PMC6061881.
40. Jankowski MP, Miller L, Koerber HR. Increased Expression of Transcription Factor SRY-box-Containing Gene 11 (Sox11) Enhances Neurite Growth by Regulating Neurotrophic Factor Responsiveness. Neuroscience. 2018 Jul 1;382:93-104. doi: 10.1016/j.neuroscience.2018.04.037. Epub 2018 May 8. PMID: 29746989; PMCID: PMC5972070.
41. Lee J, Shin JE, Lee B, Kim H, Jeon Y, Ahn SH, Chi SW, Cho Y. The stem cell marker Prom1 promotes axon regeneration by down-regulating cholesterol synthesis via Smad signaling. Proc Natl Acad Sci U S A. 2020 Jul 7;117(27):15955-15966. doi: 10.1073/pnas.1920829117. Epub 2020 Jun 17. PMID: 32554499; PMCID: PMC7355016.
42. Lindborg JA, Tran NM, Chenette DM, DeLuca K, Foli Y, Kannan R, Sekine Y, Wang X, Wollan M, Kim IJ, Sanes JR, Strittmatter SM. Optic nerve regeneration screen identifies multiple genes restricting adult neural repair. Cell Rep. 2021 Mar 2;34(9):108777. doi: 10.1016/j.celrep.2021.108777. PMID: 33657370; PMCID: PMC8009559.
43. Matson, K.J.E., Russ, D.E., Kathe, C. et al. Single cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons. Nat Commun 13, 5628 (2022). https://doi.org/10.1038/s41467-022-33184-1
44. Reverdatto S, Prasad A, Belrose JL, Zhang X, Sammons MA, Gibbs KM, Szaro BG. Developmental and Injury-induced Changes in DNA Methylation in Regenerative versus Non-regenerative Regions of the Vertebrate Central Nervous System. BMC Genomics. 2022 Jan4;23(1):2. doi: 10.1186/s12864-021-08247-0. PMID: 34979916; PMCID: PMC8725369.
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Jun 9, 2023
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Sharif Alhajlah, Mohammed Alrouji, Hamoud Alanazi, Raef Albugami, Fahad Dhawi Almutairi, & Zubair Ahmed. (2023). The role of novel genes in axon regeneration after CNS injury– A Systematic review and Meta-analysis. Journal of Population Therapeutics and Clinical Pharmacology, 30(14), 277–288. https://doi.org/10.47750/jptcp.2023.30.14.037
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