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The Journal of Neuroscience, August 20, 2003, 23(20):7602-7609

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Semaphorin 3F Antagonizes Neurotrophin-Induced Phosphatidylinositol 3-Kinase and Mitogen-Activated Protein Kinase Kinase Signaling: A Mechanism for Growth Cone Collapse

Jasvinder K. Atwal,2,3 Karun K. Singh,1 Marc Tessier-Lavigne,3 Freda D. Miller,1,2 and David R. Kaplan1,2

1The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada M5G 1X8, 2Brain Tumor Research Center and Center for Neuronal Survival, Montreal Neurological Institute, Montreal, Quebec, Canada H3A 2B4, and 3Howard Hughes Medical Institute and Department of Biological Sciences, Stanford University, Stanford, California 94305-5020

Peripheral nerve growth is regulated by the coordinated action of numerous external stimuli, including positively acting neurotrophin-derived growth cues and restrictive semaphorin cues. Here, we show that Semaphorin 3F (Sema 3F) can antagonize nerve growth factor (NGF)-stimulated TrkA (tyrosine receptor kinase A) signaling in sympathetic neurons, thereby apparently contributing to growth cone collapse. Sema 3F suppressed NGF-induced activation of the phosphatidylinositol 3 (PI3)-kinase-Akt and MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathways, both of which we show to be required to maintain growth cone structure. Sema 3F-induced growth cone collapse was partially reversed by sustained activation of the PI3-kinase and MEK pathways, which was achieved by overexpression of the Gab-1 (growth-associated binder 1) docking protein. These data indicate that a novel mechanism used by Sema 3F to collapse growth cones in sympathetic neurons is to dampen neurotrophin signaling, providing an intracellular mechanism for cross talk between positive and negative axon growth cues.

Key words: growth cone; semaphorin 3F; nerve growth factor; PI3-kinase; MEK; TrkA; signal transduction


Received Nov. 27, 2002; revised Jun. 25, 2003; accepted Jun. 26, 2003.




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