Insulin-like growth factor-I prevents apoptosis in neurons after nerve growth factor withdrawal.
Insulin-like growth factor-I (IGF-I) is emerging as an important growth factor able to modulate the programmed cell death (PCD) pathway mediated by the cysteine-dependent aspartate proteases (caspases); however, little is known about the effect of IGF-I after nerve growth factor (NGF) withdrawal in neurons. To begin to understand the neuronal death-sparing effect of IGF-I under NGF-free conditions, we tested whether embryonic sensory dorsal root ganglion neurons (DRG) were able to survive in defined serum-free medium in the presence of IGF-I. We further studied the role of IGF-I signaling and caspase inhibition after NGF withdrawal. NGF withdrawal produced histological changes of apoptosis including chromatin condensation, shrinkage of the perikaryon and nucleus, retention of the plasma membrane, and deletion of single cells. Both IGF-I and Boc-aspartyl (OMe)-fluoromethylketone (BAF), a caspase inhibitor, equally reduced apoptosis after NGF withdrawal. The antiapoptotic effect of IGF-I was completely blocked by LY294002, an inhibitor of PI 3-kinase signaling, but not by the mitogen-activated protein (MAP) kinase/extracellular signal-regulated protein kinase (ERK) activated protein kinase inhibitor PD98059. Functional IGF-I receptors were extensively expressed both in rat and human DRG neurons, although they were most abundant in the neuronal growth cone. Collectively, these findings indicate that IGF-I, signaling though the PI-3 kinase pathway, is important in modulating PCD in cultured DRG neurons after NGF withdrawal, and IGF-I may be important in DRG embryogenesis.
Russell
J W
JW
Department of Neurology, University of Michigan, Veterans Administration Medical Center, Ann Arbor 48109, USA.
Windebank
A J
AJ
Schenone
A
A
Feldman
E L
EL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology / Q000648:ultrastructure; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008854:Microscopy, Electron; D009414:Nerve Growth Factors / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009414:Nerve Growth Factors; D007334:Insulin-Like Growth Factor I