Abstract
In some diseases the TrkC.T1 isoform is upregulated in glia, associated with glial TNF-α production and neuronal death. What remains unknown are the activating signals in glia, and how paracrine signals may be selective for a targeted neuron while sparing other proximate neurons. We studied these questions in the retina, where Müller glia contacts photoreceptors on one side and retinal ganglion cells on the other. In a mutant Rhodopsin mouse model of retinitis pigmentosa (RP) causing progressive photoreceptor death-but sparing retinal ganglion cells-TrkC.T1 and NT-3 ligand are upregulated in Müller glia. TrkC.T1 activity generates p-Erk, which causes increased TNF-α. These sequential events take place predominantly in Müller fibers contacting stressed photoreceptors, and culminate in selective death. Each event and photoreceptor death can be prevented by reduction of TrkC.T1 expression, by pharmacological antagonism of TrkC or by pharmacological inhibition Erk. Unmasking the sequence of non-cell autologous events and mechanisms causing selective neuronal death may help rationalize therapies.
MeSH terms
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Animals
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Cell Death
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Disease Models, Animal
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Ependymoglial Cells / metabolism*
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Ependymoglial Cells / pathology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flavonoids / pharmacology
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Gene Expression Regulation
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HEK293 Cells
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Heterozygote
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Humans
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Mice
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Mice, Knockout
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Mutation
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Nerve Growth Factors / genetics
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Nerve Growth Factors / metabolism
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Neuroglia / metabolism
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Neuroglia / pathology
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Neurotrophin 3
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Photoreceptor Cells, Vertebrate / metabolism*
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Photoreceptor Cells, Vertebrate / pathology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rats
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Receptor, trkC / antagonists & inhibitors
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Receptor, trkC / genetics*
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Receptor, trkC / metabolism
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Retinitis Pigmentosa / genetics*
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Retinitis Pigmentosa / metabolism
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Retinitis Pigmentosa / pathology
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Rhodopsin / genetics*
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Rhodopsin / metabolism
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Signal Transduction
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Tumor Necrosis Factor-alpha / genetics*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Flavonoids
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NTF3 protein, human
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Nerve Growth Factors
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Neurotrophin 3
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RNA, Small Interfering
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Tumor Necrosis Factor-alpha
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Rhodopsin
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Receptor, trkC
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one