The activation of ezrin–radixin–moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1–induced axon outgrowth

Antoine-Bertrand, Judith; Ghogha, Atefeh; Luangrath, Vilayphone; Bedford, Fiona K.; Lamarche-Vane, Nathalie

doi:10.1091/mbc.e10-11-0917

Cited by 42 publications

(63 citation statements)

References 61 publications

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“…HEK293 cells were cultured in DMEM (Wisent Bioproducts) supplemented with 10% FBS and antibiotics. Cells were transfected overnight using PEI (PolySciences) according to the instructions of the manufacturer (16,43). Cortical neurons from embryonic day (E) 18 rat embryos (Charles River Laboratories) were dissociated mechanically and plated on dishes treated with poly-D-lysine (0.1 mg/ml, Sigma-Aldrich) or glass coverslips treated with poly-L-lysine (0.1 mg/ml, SigmaAldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Cortical neurons from embryonic day (E) 18 rat embryos (Charles River Laboratories) were dissociated mechanically and plated on dishes treated with poly-D-lysine (0.1 mg/ml, Sigma-Aldrich) or glass coverslips treated with poly-L-lysine (0.1 mg/ml, SigmaAldrich). Neurons were cultured in 10% FBS DMEM for 4 h, and the medium was replaced with Neurobasal-A medium supplemented with 2% B27 and 1% L-glutamine (Invitrogen) (16). The Amaxa rat neuron nucleofector kit (Lonza) was used according to the instructions of the manufacturer to electroporate siRNAs and plasmids.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoprecipitation-Cortical neuron (2 days in vitro (DIV)) lysates were prepared as described previously (16). Protein lysates (1 mg) were incubated with 4 g of antip120RasGAP with protein G-Sepharose beads (GE Healthcare) for 3 h at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…Neurons-We next examined the interaction of p120RasGAP and DCC in dissociated E18 rat cortical neurons, which are a good cellular model to investigate netrin-1/DCC-induced signaling pathways in the context of axon outgrowth and guidance (6,16,28,43,46,47). DCC and p120RasGAP co-immunoprecipitated, and the interaction peaked after 10 min of stimulation with netrin-1 ( ns FIGURE 2. p120RasGAP interacts with DCC in netrin-1-induced embryonic cortical neurons.…”

Section: Netrin-1 Promotes the Association Of P120rasgap With DCC In mentioning

confidence: 99%

“…Phosphorylation at C-terminal Tyr-1418 of DCC by Src family kinases is essential for netrin-1 to mediate axon outgrowth and guidance in vertebrates (13)(14)(15)(16). The significance of Tyr-1418 phosphorylation in the netrin-1/DCC signaling pathway is highlighted by its position within the P3 motif, a highly conserved region of the DCC C-terminal tail that regulates the recruitment of several proteins, including focal adhesion kinase (FAK), Src, Fyn, ezrin, and Myosin X (13)(14)(15)(16)(17)(18)(19)(20)(21).…”

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confidence: 99%

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p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Antoine-Bertrand

Duquette

Alchini

et al. 2016

Journal of Biological Chemistry

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The receptor deleted in colorectal cancer (DCC) mediates the attraction of growing axons to netrin-1 during brain development. In response to netrin-1 stimulation, DCC becomes a signaling platform to recruit proteins that promote axon outgrowth and guidance. The Ras GTPase-activating protein (GAP) p120RasGAP inhibits Ras activity and mediates neurite retraction and growth cone collapse in response to repulsive guidance cues. Here we show an interaction between p120RasGAP and DCC that positively regulates netrin-1-mediated axon outgrowth and guidance in embryonic cortical neurons. In response to netrin-1, p120RasGAP is recruited to DCC in growth cones and forms a multiprotein complex with focal adhesion kinase and ERK. We found that Ras/ERK activities are elevated aberrantly in p120RasGAP-deficient neurons. Moreover, the expression of p120RasGAP Src homology 2 (SH2)-SH3-SH2 domains, which interact with the C-terminal tail of DCC, is sufficient to restore netrin-1-dependent axon outgrowth in p120RasGAP-deficient neurons. We provide a novel mechanism that exploits the scaffolding properties of the N terminus of p120RasGAP to tightly regulate netrin-1/DCC-dependent axon outgrowth and guidance.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Netrin-1 Promotes the Association Of P120rasgap With DCC In mentioning

confidence: 99%

mentioning

confidence: 99%

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p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Antoine-Bertrand

Duquette

Alchini

et al. 2016

Journal of Biological Chemistry

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Repulsive axon guidance cues ephrin‐A2 and slit3 stop protrusion of the growth cone leading margin concurrently with inhibition of ADF/cofilin and ERM proteins

2012

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Axonal growth cones turn away from repulsive guidance cues. This may start with reduced protrusive motility in the region the growth cone leading margin that is closer to the source of repulsive cue. Using explants of E7 chick temporal retina, we examine the effects of two repulsive guidance cues, ephrin-A2 and slit3, on retinal ganglion cell growth cone protrusive activity, total F-actin, free F-actin barbed ends, and the activities (phosphorylation states) of actin regulatory proteins, ADF/cofilin and ERM proteins. Ephrin-A2 rapidly stops protrusive activity simultaneously with reducing F-actin, free barbed ends and the activities of ADF/cofilin and ERM proteins. Slit3 also stops protrusion and reduces the activities of ADF/cofilin and ERM proteins. We interpret these results as indicating that repulsive guidance cues inhibit actin polymerization and actin-membrane linkage to stop protrusive activity. Retrograde F-actin flow withdraws actin to the C-domain, where F-actin bundles interact with myosin II to generate contractile forces that can collapse and retract the growth cone. Our results suggest that common mechanisms are used by repulsive guidance cue to disable growth cone motility and remodel growing axon terminals.

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Netrin‐1 is required for efficient neural tube closure

Kee

Wilson

Key

et al. 2012

Developmental Neurobiology

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During neural tube formation, neural plate cells migrate from the lateral aspects of the dorsal surface towards the midline. Elevation of the lateral regions of the neural plate produces the neural folds which then migrate to the midline where they fuse at their dorsal tips, generating a closed neural tube comprising an apicobasally polarized neuroepithelium. Our previous study identified a novel role for the axon guidance receptor neogenin in Xenopus neural tube formation. We demonstrated that loss of neogenin impeded neural fold apposition and neural tube closure. This study also revealed that neogenin, via its interaction with its ligand, RGMa, promoted cell-cell adhesion between neural plate cells as the neural folds elevated and between neuroepithelial cells within the neural tube. The second neogenin ligand, netrin-1, has been implicated in cell migration and epithelial morphogenesis. Therefore, we hypothesized that netrin-1 may also act as a ligand for neogenin during neurulation. Here we demonstrate that morpholino knockdown of Xenopus netrin-1 results in delayed neural fold apposition and neural tube closure. We further show that netrin-1 functions in the same pathway as neogenin and RGMa during neurulation. However, contrary to the role of neogenin-RGMa interactions, neogenin-netrin-1 interactions are not required for neural fold elevation or adhesion between neuroepithelial cells. Instead, our data suggest that netrin-1 contributes to the migration of the neural folds towards the midline. We conclude that both neogenin ligands work synergistically to ensure neural tube closure.

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The activation of ezrin–radixin–moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1–induced axon outgrowth

Abstract: The axon guidance cue netrin-1 and its receptor DCC regulate axon outgrowth. Netrin-1 induces the activation of ERM proteins and their association with DCC in cortical neurons, and the activity of ERM proteins is required for netrin-1–dependent axon outgrowth.

Cited by 42 publications

References 61 publications

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

p120RasGAP Protein Mediates Netrin-1 Protein-induced Cortical Axon Outgrowth and Guidance

Repulsive axon guidance cues ephrin‐A2 and slit3 stop protrusion of the growth cone leading margin concurrently with inhibition of ADF/cofilin and ERM proteins

Netrin‐1 is required for efficient neural tube closure

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