Enhancement of sympathetic neuron survival by synergistic action of NT3 and GDNF.
Although roles of neurotrophin-3 (NT3) and glial cell line-derived neurotrophic factor (GDNF) are suggested for sympathetic neuron development, survival activity of either NT3 or GDNF alone on cultured embryonic rat sympathetic neurons is low (10-20%). We demonstrate that a combination of both NT3 and GDNF exerts a remarkable survival activity (85%). NT3 and GDNF did not affect expression levels of their receptors. However, stimulation with both NT3 and GDNF caused tyrosine-phosphorylation of Ret/GDNF-receptor at a level higher than that caused by GDNF alone. Furthermore, stimulation with both GDNF and NT3 induced an enhanced Thr308-phosphorylation of Akt kinase. These results suggest that the actions of NT3 and GDNF converge at the Ret/GDNF-receptor to enhance survival of the developing sympathetic neurons through activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway.
Kobayashi
M
M
Department of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Matsuoka
I
I
D000818:Animals; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D029721:Drosophila Proteins; D004347:Drug Interactions / Q000502:physiology*; D005333:Fetus; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D020933:Neurotrophin 3 / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D020812:Receptor, trkC / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects* / Q000196:embryology
D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC; C495041:Gdnf protein, rat; C416649:Ret protein, Drosophila; C495001:Ret protein, rat; C494920:Akt1 protein, rat