Abstract
Mutations in the X-linked gene DCX result in lissencephaly in males, and abnormal neuronal positioning in females, suggesting a role for this gene product during neuronal migration. In spite of several known protein interactions, the involvement of DCX in a signaling pathway is still elusive. Here we demonstrate that DCX is a substrate of JNK and interacts with both c-Jun N-terminal kinase (JNK) and JNK interacting protein (JIP). The localization of this signaling module in the developing brain suggests its functionality in migrating neurons. The localization of DCX at neurite tips is determined by its interaction with JIP and by the interaction of the latter with kinesin. DCX is phosphorylated by JNK in growth cones. DCX mutated in sites phosphorylated by JNK affected neurite outgrowth, and the velocity and relative pause time of migrating neurons. We hypothesize that during neuronal migration, there is a need to regulate molecular motors that are working in the cell in opposite directions: kinesin (a plus-end directed molecular motor) versus dynein (a minus-end directed molecular motor).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Brain / cytology
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Brain / embryology
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Brain / metabolism
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Cell Movement
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Cells, Cultured
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Doublecortin Domain Proteins
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Doublecortin Protein
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Growth Cones / metabolism
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Growth Cones / physiology*
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Humans
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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JNK Mitogen-Activated Protein Kinases / physiology*
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Kinesins / genetics
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Kinesins / metabolism
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Mice
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Microtubule-Associated Proteins / physiology*
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Mutagenesis, Site-Directed
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Neurites / physiology
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Neurons / metabolism
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Neurons / physiology*
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Neuropeptides / physiology*
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Phosphorylation
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Protein Binding
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Rats
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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DCX protein, human
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Dcx protein, mouse
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Dcx protein, rat
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Doublecortin Domain Proteins
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Doublecortin Protein
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Microtubule-Associated Proteins
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Neuropeptides
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JNK Mitogen-Activated Protein Kinases
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Kinesins