Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance.
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.
Briançon-Marjollet
Anne
A
CRBM-CNRS, UMR5237, 1919 Route de Mende, 34293 Montpellier Cédex 05, France.
Ghogha
Atefeh
A
Nawabi
Homaira
H
Triki
Ibtissem
I
Auziol
Camille
C
Fromont
Sylvie
S
Piché
Chantal
C
Enslen
Hervé
H
Chebli
Karim
K
Cloutier
Jean-François
JF
Castellani
Valérie
V
Debant
Anne
A
Lamarche-Vane
Nathalie
N
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured / Q000166:cytology; D002522:Chlorocebus aethiops; D000075389:DCC Receptor; D004789:Enzyme Activation; D005260:Female; D020439:Growth Cones / Q000502:physiology* / Q000648:ultrastructure; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000502:physiology*; D000075388:Netrin-1; D009479:Neuropeptides / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D054462:p21-Activated Kinases / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D020830:rac1 GTP-Binding Protein
D048868:Adaptor Proteins, Signal Transducing; D000075389:DCC Receptor; C501910:Dcc protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C000617351:NTN1 protein, human; C078332:Nck protein; D009414:Nerve Growth Factors; D009479:Neuropeptides; C000617353:Ntn1 protein, mouse; D015513:Oncogene Proteins; D010750:Phosphoproteins; C484602:Rac1 protein, mouse; D011956:Receptors, Cell Surface; C490975:Trio protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; C515905:Pak1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein