SIGNALING EVENTS REGULATING THE RETROGRADE AXONAL-TRANSPORT OF I-125 BETA-NERVE GROWTH-FACTOR IN-VIVO

The molecular mechanisms regulating the retrograde axonal transport of nerve growth factor (NGF) are currently unknown. This study identifie s some of the signalling events involved. The phosphoinositide 3-kinas e (PI3-kinase) inhibitor wortmannin (1 nmol/eye) irreversibly inhibits the amount of I-125 - beta NGF retrogradely transported in both senso ry and sympathetic neurons. Another PI3-kinase inhibitor LY294002 (100 nmol/eye) also inhibited I-125 - beta NGF retrograde transport in sen sory neurons. The pp70(S6K) inhibitor rapamycin (1 mu mol/eye) had the same effect, inhibiting I-125 - beta NGF transport only in sensory ne urons. The cPLA(2) inhibitor AACOCF(3) (10 nmol/eye) had no effect on I-125 - beta NGF transport in either sensory or sympathetic neurons. T he TrkA receptor tyrosine kinase inhibitor AG-879 (10 nmol/eye) reduce d I-125 - beta NGF transport by approximately 50% in both sensory and sympathetic neurons. Cytochalasin D (2 nmol/eye), a disrupter of actin filaments and the dynein ATPase inhibitor erythro-9-[3-(2-hydroxynony l)]adenine (EHNA) both inhibited I-125 - beta NGF retrograde transport . These results demonstrate that in vivo TrkA tyrosine kinase activity , actin filaments and dynein are involved in the retrograde transport of NGF. In addition, different PI3-kinase isoforms may be recruited wi thin different neuronal populations to regulate the retrograde transpo rt of NGF. Potentially, these isoforms could activate alternative sign alling pathways, such as pp70S6K in sensory neurons. (C) 1998 Elsevier Science B.V. All rights reserved.