Evidence for phosphatidylinositol 4-kinase and actin involvement in the regulation of I-125-beta-nerve growth factor retrograde axonal transport

The signaling events regulating the retrograde axonal transport of neurotro phins are poorly understood, but a role for phosphatidylinositol kinases ha s been proposed. In this study, we used phenylarsine oxide (PAO) to examine the participation of phosphatidylinositol 4-kinases in nerve growth factor (NGF) retrograde axonal transport within sympathetic and sensory neurons. The retrograde transport of I-125-labeled beta NGF was inhibited by PAO (0. 5-2 nmol/eye), and this effect was diminished by dilution. Coinjection of 2 ,3-dimercaptopropanol with PAO reduced its ability to inhibit I-125-beta NG F retrograde transport. PAO (20 nM to 200 mu M) also inhibited NGF-dependen t survival of both sympathetic and sensory neuronal populations. F-actin st aining in sympathetic and sensory neuronal growth cones was disrupted by PA O at 10 and 2 nM, respectively, and occurred within 5 min of exposure to th e drug. The actin inhibitor latrunculin A also rapidly affected F-actin sta ining in vitro and reduced I-125-beta NGF retrograde axonal transport in vi vo to the same extent as PAO. These results suggest that both phosphatidyli nositol 4-kinase isoforms and the actin cytoskeleton play significant roles in the regulation of I-125-beta NGF retrograde axonal transport in vivo.