Abstract
Axon guidance requires signal transduction of extracellular cues through the plasma membrane for directional motility. Here we present evidence that cholesterol- and sphingolipid-enriched membrane microdomains (lipid rafts) mediate specific guidance responses of nerve growth cones. Disruption of lipid rafts by various approaches targeting cholesterol or gangliosides selectively abolished growth cone attraction and repulsion in BDNF and netrin-1 gradients, respectively, without affecting glutamate-induced attraction. Interestingly, local raft disruption on one side of the growth cone in bath BDNF or netrin-1 produced opposite turning responses to that induced by the gradients. Raft manipulation also blocked Semaphorin 3A-induced growth cone repulsion, inhibition, and collapse. Finally, guidance responses appeared to involve raft-dependent activation of p42/p44 MAPK and ligand-induced receptor recruitment to lipid rafts. Together with the observation of asymmetric receptor-raft associations at the growth cone in guidance gradients, our findings indicate that localized signaling through membrane rafts plays a role in mediating guidance actions of extracellular cues on developing axons.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies / pharmacology
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Antigens / immunology
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Antigens / metabolism
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Blotting, Western / methods
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Brain Stem / cytology
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Brain-Derived Neurotrophic Factor / pharmacology
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Cell Adhesion Molecules / metabolism
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Cells, Cultured
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Cholera Toxin / pharmacology
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Cholesterol / pharmacology
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Cytoskeletal Proteins / antagonists & inhibitors
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Cytoskeletal Proteins / immunology
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Cytoskeletal Proteins / metabolism
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DCC Receptor
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Drug Interactions
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Filipin / pharmacology
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Flavonoids / pharmacology
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Fluorescent Antibody Technique / methods
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Glutamic Acid / pharmacology
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Growth Cones / drug effects
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Growth Cones / physiology*
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Image Processing, Computer-Assisted
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Membrane Microdomains / drug effects
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Membrane Microdomains / physiology*
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Mucin-5B
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Mucins / pharmacology
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Nerve Growth Factors / pharmacology
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Netrin-1
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Neurons / cytology
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Neurons / drug effects
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Neurons / physiology*
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Neuropilin-1 / metabolism
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Peptides / pharmacology
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Receptor, trkB / metabolism
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Receptors, Cell Surface
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Receptors, N-Methyl-D-Aspartate / metabolism
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Semaphorins / physiology
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Signal Transduction / physiology*
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Statistics, Nonparametric
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Tumor Suppressor Proteins / metabolism
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Xenopus
Substances
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Antibodies
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Antigens
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Brain-Derived Neurotrophic Factor
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Cell Adhesion Molecules
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Cytoskeletal Proteins
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DCC Receptor
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DCC protein, human
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Flavonoids
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IFI44 protein, human
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MUC5B protein, human
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Mucin-5B
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Mucins
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NR2B NMDA receptor
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NTN1 protein, human
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Nerve Growth Factors
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Peptides
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Receptors, Cell Surface
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Receptors, N-Methyl-D-Aspartate
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Semaphorins
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Tumor Suppressor Proteins
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Neuropilin-1
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Netrin-1
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mast cell degranulating peptide
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Glutamic Acid
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Filipin
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Cholera Toxin
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Cholesterol
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Receptor, trkB
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one