GDNF family ligands trigger indirect neuroprotective signaling in retinal glial cells.
Apoptotic cell death of photoreceptors is the final event leading to blindness in the heterogeneous group of inherited retinal degenerations. GDNF (glial cell-line-derived neurotrophic factor) was found to rescue photoreceptor function and survival very effectively in an animal model of retinal degeneration (M. Frasson, S. Picaud, T. Leveillard, M. Simonutti, S. Mohand-Said, H. Dreyfus, D. Hicks, and J. Sahel, Investig. Ophthalmol. Vis. Sci. 40:2724-2734, 1999). However, the cellular mechanism of GDNF action remained unresolved. We show here that in porcine retina, GDNF receptors GFRalpha-1 and RET are expressed on retinal Mueller glial cells (RMG) but not on photoreceptors. Additionally, RMG express the receptors for the GDNF family members artemin and neurturin (GFRalpha-2 and GFRalpha-3). We further investigated GDNF-, artemin-, and neurturin-induced signaling in isolated primary RMG and demonstrate three intracellular cascades, which are activated in vitro: MEK/ERK, stress-activated protein kinase (SAPK), and PKB/AKT pathways with different kinetics in dependence on stimulating GFL. We correlate the findings to intact porcine retina, where GDNF induces phosphorylation of ERK in the perinuclear region of RMG located in the inner nuclear layer. GDNF signaling resulted in transcriptional upregulation of FGF-2, which in turn was found to support photoreceptor survival in an in vitro assay. We provide here a detailed model of GDNF-induced signaling in mammalian retina and propose that the GDNF-induced rescue effect on mutated photoreceptors is an indirect effect mediated by retinal Mueller glial cells.
GSF-National Research Center for Environment and Health, Institute of Human Genetics, Ingolstaedter Landstrasse 1, 85764 Munich-Neuherberg, Germany.
Stefanie M
SM
Hauck
Norbert
N
Kinkl
Cornelia A
CA
Deeg
Magdalena
M
Swiatek-de Lange
Stephanie
S
Schöffmann
Marius
M
Ueffing
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D051101:Neurturin / Q000378:metabolism; D010766:Phosphorylation; D010786:Photoreceptor Cells / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D015854:Up-Regulation / Q000235:genetics
D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D018696:Neuroprotective Agents; D051101:Neurturin; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases