1. ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway
- Author
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Olivier De Backer, Adriana Di Polo, Frédéric Lebrun-Julien, Carlos R. Morales, Mathieu J.M. Bertrand, Philip A. Barker, and David Stellwagen
- Subjects
Retinal Ganglion Cells ,Apoptosis ,Mice, Transgenic ,Biology ,Retinal ganglion ,Receptor, Nerve Growth Factor ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Nerve Growth Factor ,medicine ,Low-affinity nerve growth factor receptor ,Animals ,Retina ,Multidisciplinary ,Tumor Necrosis Factor-alpha ,Retinal ,Anatomy ,Biological Sciences ,Cell biology ,Rats ,Mice, Inbred C57BL ,Adaptor Proteins, Vesicular Transport ,medicine.anatomical_structure ,Nerve growth factor ,nervous system ,Retinal ganglion cell ,chemistry ,Neurotrophin binding ,sense organs ,Signal transduction ,Signal Transduction - Abstract
Neurotrophin binding to the p75 neurotrophin receptor (p75 NTR ) activates neuronal apoptosis following adult central nervous system injury, but the underlying cellular mechanisms remain poorly defined. In this study, we show that the proform of nerve growth factor (proNGF) induces death of retinal ganglion cells in adult rodents via a p75 NTR -dependent signaling mechanism. Expression of p75 NTR in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cell-autonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFα) in Müller cells and that genetic or biochemical ablation of TNFα blocked proNGF-induced death of retinal neurons. Mice rendered null for p75 NTR , its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFα production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFα-dependent death of retinal neurons in vivo.
- Published
- 2010