Abstract
The chemotropic guidance cue netrin-1 promotes neurite outgrowth through its receptor Deleted in Colorectal Cancer (DCC) via activation of Rac1. The guanine nucleotide exchange factor (GEF) linking netrin-1/DCC to Rac1 activation has not yet been identified. Here, we show that the RhoGEF Trio mediates Rac1 activation in netrin-1 signaling. We found that Trio interacts with the netrin-1 receptor DCC in mouse embryonic brains and that netrin-1-induced Rac1 activation in brain is impaired in the absence of Trio. Trio(-/-) cortical neurons fail to extend neurites in response to netrin-1, while they are able to respond to glutamate. Accordingly, netrin-1-induced commissural axon outgrowth is reduced in Trio(-/-) spinal cord explants, and the guidance of commissural axons toward the floor plate is affected by the absence of Trio. The anterior commissure is absent in Trio-null embryos, and netrin-1/DCC-dependent axonal projections that form the internal capsule and the corpus callosum are defective in the mutants. Taken together, these findings establish Trio as a GEF that mediates netrin-1 signaling in axon outgrowth and guidance through its ability to activate Rac1.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Brain / abnormalities
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Brain / cytology
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Brain / embryology
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COS Cells
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Cell Line
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Cells, Cultured / cytology
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Chlorocebus aethiops
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DCC Receptor
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Enzyme Activation
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Female
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Growth Cones / physiology*
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Growth Cones / ultrastructure
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Guanine Nucleotide Exchange Factors / deficiency
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / physiology*
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Humans
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Nerve Growth Factors / physiology*
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Netrin-1
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Neuropeptides / physiology*
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Oncogene Proteins / physiology
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / physiology*
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Protein Interaction Mapping
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Receptors, Cell Surface / physiology*
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Spinal Cord / cytology
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Spinal Cord / embryology
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Tumor Suppressor Proteins / physiology*
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p21-Activated Kinases / physiology
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rac GTP-Binding Proteins / physiology*
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rac1 GTP-Binding Protein
Substances
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Adaptor Proteins, Signal Transducing
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DCC Receptor
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Dcc protein, mouse
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Guanine Nucleotide Exchange Factors
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NTN1 protein, human
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Nck protein
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Nerve Growth Factors
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Neuropeptides
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Ntn1 protein, mouse
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Oncogene Proteins
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Phosphoproteins
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Rac1 protein, mouse
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Receptors, Cell Surface
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Trio protein, mouse
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Tumor Suppressor Proteins
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Netrin-1
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Pak1 protein, mouse
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein