Signalling events regulating the retrograde axonal transport of 125I-beta nerve growth factor in vivo.
The molecular mechanisms regulating the retrograde axonal transport of nerve growth factor (NGF) are currently unknown. This study identifies some of the signalling events involved. The phosphoinositide 3-kinase (PI3-kinase) inhibitor wortmannin (1 nmol/eye) irreversibly inhibits the amount of 125I-betaNGF retrogradely transported in both sensory and sympathetic neurons. Another PI3-kinase inhibitor LY294002 (100 nmol/eye) also inhibited 125I-betaNGF retrograde transport in sensory neurons. The pp70S6K inhibitor rapamycin (1 micromol/eye) had the same effect, inhibiting 125I-betaNGF transport only in sensory neurons. The cPLA2 inhibitor AACOCF3 (10 nmol/eye) had no effect on 125I-betaNGF transport in either sensory or sympathetic neurons. The TrkA receptor tyrosine kinase inhibitor AG-879 (10 nmol/eye) reduced 125I-betaNGF transport by approximately 50% in both sensory and sympathetic neurons. Cytochalasin D (2 nmol/eye), a disruptor of actin filaments and the dynein ATPase inhibitor erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA) both inhibited 125I-betaNGF 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 within different neuronal populations to regulate the retrograde transport of NGF. Potentially, these isoforms could activate alternative signalling pathways, such as pp70S6K in sensory neurons.
Developmental Neurobiology, Division of Neuroscience, The John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra, ACT 2601, Australia. reynolds@jcsmr.anu.edu.au
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Reynolds
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Bartlett
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Hendry
D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D004398:Dyneins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000493:pharmacokinetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D004398:Dyneins