Abstract
Growing axons navigate by responding to chemical guidance cues. Here we report that growth cones of rat cerebellar axons in culture turned away from a gradient of SDF-1, a chemokine that attracts migrating leukocytes and cerebellar granule cells via a G protein-coupled receptor (GPCR). Similarly, Xenopus spinal growth cones turned away from a gradient of baclofen, an agonist of the GABA(B) receptor. This response was mediated by G(i) and subsequent activation of phospholipase C (PLC), which triggered two pathways: protein kinase C (PKC) led to repulsion, and inositol 1,4,5-triphosphate (IP(3)) receptor activation led to attractive turning. Under normal culture conditions, PKC-dependent repulsion dominated, but the repulsion could be converted to attraction by inhibiting PKC or by elevating cytosolic cGMP. Thus, GPCRs can mediate both repulsive and attractive axon guidance in vitro, and chemokines may serve as guidance cues for axon pathfinding.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminocaproic Acid / antagonists & inhibitors
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Aminocaproic Acid / metabolism
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Animals
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Baclofen / pharmacology
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Cell Communication / physiology*
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Cell Differentiation / physiology*
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Cells, Cultured
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Central Nervous System / cytology
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Central Nervous System / embryology*
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Central Nervous System / metabolism
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Cerebellar Cortex / cytology
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Cerebellar Cortex / embryology
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Cerebellar Cortex / metabolism
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Chemokine CXCL12
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Chemokines / metabolism*
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Chemokines, CXC / metabolism
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Chemokines, CXC / pharmacology
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Chemotaxis / drug effects
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Chemotaxis / physiology
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Cyclic GMP / metabolism
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GABA Agonists / pharmacology
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GABA-B Receptor Agonists
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GABA-B Receptor Antagonists
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GTP-Binding Proteins / metabolism*
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Growth Cones / metabolism*
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Growth Cones / ultrastructure
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Inositol 1,4,5-Trisphosphate / metabolism
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Protein Kinase C / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Cell Surface / metabolism*
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Receptors, GABA-B / metabolism
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Signal Transduction / physiology
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Type C Phospholipases / metabolism
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Xenopus laevis
Substances
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Chemokine CXCL12
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Chemokines
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Chemokines, CXC
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GABA Agonists
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GABA-B Receptor Agonists
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GABA-B Receptor Antagonists
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Receptors, Cell Surface
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Receptors, GABA-B
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Inositol 1,4,5-Trisphosphate
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Protein Kinase C
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Type C Phospholipases
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GTP-Binding Proteins
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Cyclic GMP
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Baclofen
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Aminocaproic Acid