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Z. Yang, H. A. Quigley, D. J. Zack; Neuritin - A Novel Retinal Ganglion Cell Neurotrophic Factor With Therapeutic Potential. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3087.
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© ARVO (1962-2015); The Authors (2016-present)
We have been taking a variety of approaches to investigate the molecular basis of retinal ganglion cell (RGC) death in glaucoma and optic nerve injury. As part of this work, we evaluated the role of Neuritin (Nrn1) in the survival and neurite growth of cultured RGCs and its possible role in pressure-induced RGC degeneration in a rodent model of glaucoma.
We employed a microarray-based approach to profile retinal gene expression changes in a rat glaucoma model and after optic nerve transection. Microarray findings were confirmed by quantitative RT-PCR and in situ hybridization. Additional studies were performed on Nrn1, one of the genes that is down-regulated in the rat glaucoma model and optic nerve transection. Nrn1 is a neuron-specific gene that has been implicated in neuronal survival and axonal regeneration. The biological activity of NRN1 protein was explored using purified primary murine RGCs and retinal explants. We have also begun to study the upstream regulatory mechanisms controlling Nrn1 expression, and the signal transductions mechanisms mediating NRN1 action.
Our results show that Nrn1 is specifically expressed by RGCs within the retina and that its expression is promptly downregulated by experimental IOP elevation and optic nerve transection. Exogenous NRN1 protein strongly promotes the survival of purified mouse RGCs and stimulates neurite outgrowth. Nrn1 expression in RGCs is positively regulated by neurotrophin signaling. Moreover, the transcription factor Pou4f2 appears to be necessary for Nrn1 expression in RGCs. In addition, preliminary data suggests that the cGMP/PKG signaling pathway may be important in mediating the neurite-promoting activity of NRN1.
Our results suggest that Nrn1 may function as an RGC-secreted trophic factor. Experimental IOP elevation and axonal injury can both downregulate its expression, and this down-regulation may be regulated through a decrease in neurotrophin signaling and altered Pou4f2 expression. Taken together, our findings are consistent with the hypothesis that IOP elevation and axonal injury, possibly through decreased axonal transport, may lead to RGC death through a deficiency in trophic support for RGCs, and that decreased expression of NGN1 may play a role in this mechanism.
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