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The Journal of Neuroscience, February 15, 2003, 23(4):1360
A Chemokine, SDF-1, Reduces the Effectiveness of Multiple Axonal Repellents and Is Required for Normal Axon Pathfinding
Sreekanth H. Chalasani1, Kimberly A. Sabelko1, Mary J. Sunshine2, Dan R. Littman2, and Jonathan A. Raper1 1 Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and 2 Howard Hughes Medical Institute, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016
Altering the concentrations of cyclic nucleotides within nerve cells can dramatically change their responses to axonal guidance cues, but the physiological signals that might induce such alterations are unknown. Here we show that the chemokine stromal cell-derived factor 1 (SDF-1) reduces the repellent activities of slit-2 on cultured retinal ganglion cell axons, of semaphorin 3A on dorsal root ganglion sensory axons, and of semaphorin 3C on sympathetic axons. This is a modulatory effect because SDF-1 has no detectable attractive or repellent effects on retinal or DRG axons by itself. This modulation is mediated through CXCR4, the receptor of SDF-1, and a pertussis toxin-sensitive G-protein-coupled signaling pathway that induces an elevation of cAMP. The spinal cords of CXCR4 mutant mice contain hyperfasciculated and aberrantly projecting axons. These results suggest that SDF-1 plays an essential role in modulating axonal responsiveness to various known guidance cues through a cyclic nucleotide-dependent signaling pathway.
Key words: axon guidance; growth cone; SDF-1; slit-2; semaphorin 3A; semaphorin 3C; repellents; modulation; cAMP; retina; sensory; sympathetic
Copyright © 2003 Society for Neuroscience 0270-6474/03/2341360-12$05.00/0
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