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Nrn1 Overexpression Attenuates Retinal Ganglion Cell Apoptosis, Promotes Axonal Regeneration, and Improves Visual Function Following Optic Nerve Crush in Rats

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Abstract

Neuritin (Nrn1) is a small highly conserved extracellular membrane protein involved in the process of neural cell survival and differentiation, axonal and dendritic growth, and synapse formation and maturation. Previous studies have demonstrated that intravitreal injection of recombinant Nrn1 as a gene therapy could alleviate retinal ganglion cell (RGC) apoptosis and promote optic nerve axon regeneration after optic nerve crush (ONC). However, the mechanism underlying the repairing effect of Nrn1 against optic never injury remains elusive. In this study, a rAAV2-mediated Nrn1 overexpression vector (AAV2-Nrn1) was applied to treat ONC through intravitreal injection for the purpose of further exploring the effect and mechanism of Nrn1 in repairing the injured optic nerve. The results showed that AAV2-Nrn1 was mainly transfected into RGCs without affecting astrocytes. Nrn1 overexpression effectively reduced RGC apoptosis and promoted optic nerve regeneration and visual function restoration as demonstrated by retinal imaging, histopathological analysis, and physiological function detection in vivo following ONC. Immunoblot assay revealed that functional molecules of Nrn1 activated the Akt1 and Stat3 pathways and inhibited the mitochondrial apoptotic pathway. The results of the present study may provide experimental evidence for further application of Nrn1 to the clinical treatment of optic nerve injury.

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Funding

This present study was supported by the National Natural Science Foundation of China under award number 31271282.

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  1. Tingting Huang and He Li contributed equally to this work.

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  1. Department of Anatomy, Second Military Medical University, Shanghai, 200433, People’s Republic of China

    Tingting Huang, He Li, Shoumei Zhang, Fang Liu, Dong Wang & Jiajun Xu

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  1. Tingting Huang
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Contributions

JX designed this study. TH and HL acquired the data and wrote a draft of the manuscript; TH, SZ, and HL prepared the experiment materials and performed the animal experiment and in vivo assays; FL and DW interpreted data, performed the statistical analysis, and analyzed the results; JX revised the manuscript. All the authors approved and read final manuscript.

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Correspondence to Jiajun Xu.

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Huang, T., Li, H., Zhang, S. et al. Nrn1 Overexpression Attenuates Retinal Ganglion Cell Apoptosis, Promotes Axonal Regeneration, and Improves Visual Function Following Optic Nerve Crush in Rats. J Mol Neurosci 71, 66–79 (2021). https://doi.org/10.1007/s12031-020-01627-3

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