A chemokine, SDF-1, reduces the effectiveness of multiple axonal repellents and is required for normal axon pathfinding.
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.
Chalasani
Sreekanth H
SH
Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Sabelko
Kimberly A
KA
Sunshine
Mary J
MJ
Littman
Dan R
DR
Raper
Jonathan A
JA
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology*; D002642:Chick Embryo; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D020439:Growth Cones / Q000187:drug effects / Q000648:ultrastructure; D036341:Intercellular Signaling Peptides and Proteins; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects; D039961:Semaphorins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000502:physiology; D000098552:Slit Homolog 2 Protein
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D017362:Cyclic AMP Response Element-Binding Protein; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D019718:Receptors, CXCR4; D039961:Semaphorins; D000242:Cyclic AMP; D020741:rho GTP-Binding Proteins; D000098552:Slit Homolog 2 Protein