ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway

Frédéric Lebrun-Julien, Mathieu J Bertrand, Olivier De Backer, David Stellwagen, Carlos R Morales, Adriana Di Polo, Philip A Barker

Research output: Contribution to journalArticle

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 (TNFalpha) in Müller cells and that genetic or biochemical ablation of TNFalpha 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 TNFalpha production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFalpha-dependent death of retinal neurons in vivo.
Original languageEnglish
Pages (from-to)3817-22
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number8
DOIs
Publication statusPublished - 2010

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Retinal Ganglion Cells
Nerve Growth Factor
Tumor Necrosis Factor-alpha
Nerve Growth Factor Receptor
Retinal Neurons
Neuroglia
Cell Death
Nervous System Trauma
Nerve Growth Factors
Retina
Molecular Biology
Rodentia
Central Nervous System
Apoptosis

Cite this

Lebrun-Julien, Frédéric ; Bertrand, Mathieu J ; De Backer, Olivier ; Stellwagen, David ; Morales, Carlos R ; Di Polo, Adriana ; Barker, Philip A. / ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 8. pp. 3817-22.
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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 M{\"u}ller 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 (TNFalpha) in M{\"u}ller cells and that genetic or biochemical ablation of TNFalpha 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 TNFalpha production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFalpha-dependent death of retinal neurons in vivo.",
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ProNGF induces TNFalpha-dependent death of retinal ganglion cells through a p75NTR non-cell-autonomous signaling pathway. / Lebrun-Julien, Frédéric; Bertrand, Mathieu J; De Backer, Olivier; Stellwagen, David; Morales, Carlos R; Di Polo, Adriana; Barker, Philip A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 8, 2010, p. 3817-22.

Research output: Contribution to journalArticle

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AU - Lebrun-Julien, Frédéric

AU - Bertrand, Mathieu J

AU - De Backer, Olivier

AU - Stellwagen, David

AU - Morales, Carlos R

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AU - Barker, Philip A

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AB - 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 (TNFalpha) in Müller cells and that genetic or biochemical ablation of TNFalpha 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 TNFalpha production and did not undergo proNGF-induced retinal ganglion cell death. We conclude that proNGF activates a non-cell-autonomous signaling pathway that causes TNFalpha-dependent death of retinal neurons in vivo.

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