Insulin-like growth factor-I is a potential trophic factor for amacrine cells.
In this study we show that insulin-like growth factor (IGF)-I selectively promotes survival and differentiation of amacrine neurons. In cultures lacking this factor, an initial degeneration pathway, selectively affecting amacrine neurons, led to no lamellipodia development and little axon outgrowth. Cell lysis initially affected 50% of amacrine neurons; those remaining underwent apoptosis leading to the death of approximately 95% of them by day 10. Apoptosis was preceded by a marked increase in c-Jun expression. Addition of IGF-I or high concentrations (over 1 microM) of either insulin or IGF-II to the cultures prevented the degeneration of amacrine neurons, stimulated their neurite outgrowth, increased phospho-Akt expression and decreased c-Jun expression. The high insulin and IGF-II concentrations required to protect amacrine cells suggest that these neurons depend on IGF-I for their survival, IGF-II and insulin probably acting through IGF-I receptors to mimic IGF-I effects. Inhibition of phosphatidylinositol-3 kinase (PI 3-kinase) with wortmannin blocked insulin-mediated survival. Wortmannin addition had similar effects to IGF-I deprivation: it prevented neurite outgrowth, increased c-Jun expression and induced apoptosis. These results suggest that IGF-I is essential for the survival and differentiation of amacrine neurons, and activation of PI 3-kinase is involved in the intracellular signaling pathways mediating these effects.
Politi
L E
LE
Instituto de Investigaciones Bioquímicas de Bahía Blanca, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Buenos Aires, Argentina.
Rotstein
N P
NP
Salvador
G
G
Giusto
N M
NM
Insua
M F
MF
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D011554:Pseudopodia / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D007328:Insulin; D007329:Insulin Antagonists; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D000077191:Wortmannin; C494920:Akt1 protein, rat