Inhibition of p75(NTR) in glia potentiates TrkA-mediated survival of injured retinal ganglion cells.
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 Müller 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.
Lebrun-Julien
Frédéric
F
Department of Pathology and Cell Biology and Groupe de Recherche sur le Système Nerveux Central (GRSNC), Université de Montréal, 2900 Boulevard Edouard-Montpetit Pavillon Roger-Gaudry, Room S-520, Montreal, Quebec H3T1J4, Canada.
Morquette
Barbara
B
Douillette
Annie
A
Saragovi
H Uri
HU
Di Polo
Adriana
A
D000818:Animals; D019771:Axotomy; D002470:Cell Survival / Q000502:physiology*; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D020932:Nerve Growth Factor / Q000819:agonists / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009900:Optic Nerve / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology*
D008024:Ligands; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C068313:Ngfr protein, rat; D020932:Nerve Growth Factor; D020917:Receptor, trkA