ProNGF Induces TNFα-Dependent Death of Retinal Ganglion Cells through a$p75^{NTR} $Non-Cell-Autonomous Signaling Pathway

Neurotrophin binding to the p75 neurotrophin receptor ${\rm{(p75}}^{{\rm{NTR}}} )$ 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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2010-02, Vol.107 (8), p.3817-3822
Main Authors: Lebrun-Julien, Frédéric, Bertrand, Mathieu J., de Backer, Olivier, Stellwagen, David, Morales, Carlos R., di Polo, Adriana, Barker, Philip A., Chao, Moses V.
Format: Article
Language:English
Subjects:
Antibodies
Apoptosis
Cell death
Ganglia
Neuroglia
Neurons
Neuroscience
Photoreceptors
Receptors
Retina
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container_issue 8
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container_title Proceedings of the National Academy of Sciences - PNAS
container_volume 107
creator Lebrun-Julien, Frédéric
Bertrand, Mathieu J.
de Backer, Olivier
Stellwagen, David
Morales, Carlos R.
di Polo, Adriana
Barker, Philip A.
Chao, Moses V.
description Neurotrophin binding to the p75 neurotrophin receptor ${\rm{(p75}}^{{\rm{NTR}}} )$ 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 ${\rm{p75}}^{{\rm{NTR}}} $ -dependent signaling mechanism. Expression of ${\rm{p75}}^{{\rm{NTR}}} $ in the adult retina is confined to Müller glial cells; therefore we tested the hypothesis that proNGF activates a non-cellautonomous signaling pathway to induce retinal ganglion cell (RGC) death. Consistent with this, we show that proNGF induced robust expression of tumor necrosis factor alpha (TNFa) in Müller cells and that genetic or biochemical ablation of TNFa blocked proNGF-induced death of retinal neurons. Mice rendered null for ${\rm{p75}}^{{\rm{NTR}}} $ , its coreceptor sortilin, or the adaptor protein NRAGE were defective in proNGF-induced glial TNFa production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFa-dependent death of retinal neurons in vivo.
doi_str_mv 10.1073/pnas.0909276107
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subjects Antibodies
Apoptosis
Cell death
Ganglia
Neuroglia
Neurons
Neuroscience
Photoreceptors
Receptors
Retina
title ProNGF Induces TNFα-Dependent Death of Retinal Ganglion Cells through a$p75^{NTR} $Non-Cell-Autonomous Signaling Pathway
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