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 growt h factor able to modulate the programmed cell death (PCD) pathway medi ated 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 surv ive in defined serum-free medium in the presence of IGF-I. We further studied the role of IGF-I signaling and caspase inhibition after NGP w ithdrawal. NGF withdrawal produced histological changes of apoptosis i ncluding chromatin condensation, shrinkage of the perikaryon and nucle us, retention of the plasma membrane, and deletion of single cells. Bo th IGF-I and Boc-aspartyl (OMe)-fluoromethylketone (BAF), a caspase in hibitor, equally reduced apoptosis after NGF withdrawal. The antiapopt otic effect of IGF-I was completely blocked by LY294002, an inhibitor of PI3-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 ext ensively expressed both in rat and human DRG neurons, although they we re most abundant in the neuronal growth cone. Collectively, these find ings indicate that IGF-I, signaling though the PI-3 kinase pathway, is important in modulating PCD in cultured DRG neurons after NGF withdra wal, and IGF-I may be important in DRG embryogenesis. (C) 1998 John Wi ley & Sons, Inc.