Purchase this article with an account.
Tasneem Putliwala Sharma, Yang Liu, Iok-Hou Pang, Robert J Wordinger, Abbot F Clark; Neuritin1 Promotes Retinal Ganglion Cell Survival And Axonal Regeneration Following Optic Nerve Crush. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2669.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Glaucoma is a progressive optic neuropathy characterized by axonal injury, retinal ganglion cell (RGC) loss, and visual field defects. Neuritin1 (Nrn1), an extracellular GPI-linked protein, stimulates axonal plasticity, dendritic arborization, and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized RGCs in vitro and the optic nerve crush (ONC) mouse model in vivo for promoting survival and visual function of RGCs.
In vitro axotomized RGCs were treated for 10 days with recombinant hNrn1 (200ng/ml), and evaluated for survival and neurite outgrowth by immuno-staining for Rbpms and Nefl. Unilateral ONC was performed on adult BALB/cJ mouse eyes transduced with either AAV2-CAG-hNRN1 (“tx” group) or AAV2-CAG-GFP (“ctrl” group). Visual function was assessed using flash ERG (pSTR) weekly till 28 days post crush (dpc). Retinas and ONs were harvested weekly and immuno-stained for the RGC marker Brn3a to assess survival of RGCs and Gap43/Nrn1 to evaluate axon regeneration. Retinas were also harvested 28 dpc to assess protein expression of Nrn1, Rbpms and Gap43 by Western blotting.
Recombinant hNrn1 significantly increased survival of RGCs by 22% (n=8, p<0.01) and neurite outgrowth of cultured RGC. In the in vivo ONC model, AAV2-CAG-hNRN1 promoted RGC survival by 58% (7% in ctrl vs 12% in tx group, n=3) and significantly preserved visual function of RGCs by 41% until 28 dpc (n=6, p<0.05) compared to the ctrl group. Increased expression of Gap43 and Nrn1 was observed in the ganglion cell layer and inner plexiform layer of retina and crush sites of ON sections in the tx group. Significantly elevated levels of Nrn1 (54.8 ± 8.5%), Rbpms (12.32 ± 0.3%) and Gap43 (58.2 ± 0.1%) (n=3, p<0.05) were observed 28 dpc in the tx group compared to the ctrl group.
Nrn1 exhibited neuroprotective and regenerative effects on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases.
This PDF is available to Subscribers Only