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Inhibition of p75(NTR) in glia potentiates TrkA-mediated survival of injured retinal ganglion cells
- Source :
- Molecular and cellular neurosciences. 40(4)
- Publication Year :
- 2008
-
Abstract
- Little is known about the molecular mechanisms that limit the ability of retinal neurons to respond to neurotrophic factor stimulation following axonal injury. In the adult retina, nerve growth factor (NGF) binds to TrkA (expressed by neurons) and p75(NTR) (expressed by Muller glia), but fails to promote the survival of axotomized retinal ganglion cells (RGCs). We addressed the functional role of TrkA and p75(NTR) in this lack of survival by using peptidomimetic agonistic or antagonistic ligands specific for each receptor. While administration of exogenous NGF failed to rescue axotomized RGCs, administration of selective TrkA agonists led to robust neuroprotection. Surprisingly, we found a remarkable survival of axotomized RGCs following pharmacological inhibition of p75(NTR) or in p75(NTR) knockout mice. Combination of NGF or TrkA agonists with p75(NTR) antagonists further potentiated RGC neuroprotection in vivo, an effect that was greater than each treatment alone. NGF can therefore be neuroprotective when acting on neuronal TrkA receptors but engagement of p75(NTR) on glial cells antagonizes this effect. Our data reveal a novel mechanism by which p75(NTR) expressed on retinal glia can profoundly influence neuronal survival.
- Subjects :
- Retinal Ganglion Cells
Cell Survival
Nerve Tissue Proteins
Receptors, Nerve Growth Factor
Tropomyosin receptor kinase A
Biology
Ligands
Retinal ganglion
Neuroprotection
Rats, Sprague-Dawley
Cellular and Molecular Neuroscience
Mice
Neurotrophic factors
Nerve Growth Factor
medicine
Low-affinity nerve growth factor receptor
Animals
Humans
Receptors, Growth Factor
Receptor, trkA
Molecular Biology
Mice, Knockout
Retina
Axotomy
Optic Nerve
Cell Biology
Rats
medicine.anatomical_structure
Nerve growth factor
nervous system
Female
sense organs
Muller glia
Neuroscience
Neuroglia
Subjects
Details
- ISSN :
- 10959327
- Volume :
- 40
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Molecular and cellular neurosciences
- Accession number :
- edsair.doi.dedup.....855d9a22cd5e3163dcc01bf20494d91d