CED-10/Rac1 Mediates Axon Guidance by Regulating the Asymmetric Distribution of MIG-10/Lamellipodin

Quinn, Christopher C.; Pfeil, Douglas S.; Wadsworth, William G.

doi:10.1016/j.cub.2008.04.050

Cited by 71 publications

(86 citation statements)

References 30 publications

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“…We have proposed that a signaling module comprising UNC-6, UNC-40, PI3K, Rac, and MIG-10 (lamellipodin) becomes asymmetrically localized in the C. elegans AVM and HSN neurons Chang et al 2006;Quinn et al 2006Quinn et al , 2008. This localization is proposed to polarize the response and to amplify the shallow external UNC-6 gradient.…”

Section: Resultsmentioning

confidence: 99%

“…In AVM and HSN, a signaling module comprising UNC-6, UNC-40, phosphoinositide 3-kinase (PI3K), Rac, and MIG-10 (lamellipodin) is thought to transmit the directional information provided by the graded distribution of extracellular guidance cues to the internal cellular machinery that promotes directed outgrowth Chang et al 2006;Quinn et al 2006Quinn et al , 2008. MIG-10 appears to provide an important link because this family of proteins can interact with proteins that promote actin polymerization, and it is associated with asymmetric concentrations of f-actin and microtubules in turning growth cones (Krause et al 2004;Quinn et al 2008).…”

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confidence: 99%

“…MIG-10 appears to provide an important link because this family of proteins can interact with proteins that promote actin polymerization, and it is associated with asymmetric concentrations of f-actin and microtubules in turning growth cones (Krause et al 2004;Quinn et al 2008). MIG-10 is observed as asymmetrically localized to the ventral site of axon outgrowth in developing HSN neurons.…”

mentioning

confidence: 99%

“…The UNC-40 receptor is also asymmetrically localized in HSN, and this localization is also dependent on UNC-6 . UNC-40 signaling activates Rac GTPase, and MIG-10 interacts specifically with the activated Rac (Quinn et al 2008). Therefore, the asym-metric activation of Rac through UNC-40 recruits asymmetric MIG-10 localization.…”

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confidence: 99%

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The Roles of Multiple UNC-40 (DCC) Receptor-Mediated Signals in Determining Neuronal Asymmetry Induced by the UNC-6 (Netrin) Ligand

Xu¹,

Li²,

Wadsworth³

2009

Genetics

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The polarization of post-mitotic neurons is poorly understood. Preexisting spatially asymmetric cues, distributed within the neuron or as extracellular gradients, could be required for neurons to polarize. Alternatively, neurons might have the intrinsic ability to polarize without any preestablished asymmetric cues. In Caenorhabditis elegans, the UNC-40 (DCC) receptor mediates responses to the extracellular UNC-6 (netrin) guidance cue. For the HSN neuron, an UNC-6 ventral-dorsal gradient asymmetrically localizes UNC-40 to the ventral HSN surface. There an axon forms, which is ventrally directed by UNC-6. In the absence of UNC-6, UNC-40 is equally distributed and the HSN axon travels anteriorly in response to other cues. However, we find that a single amino acid change in the UNC-40 ectodomain causes randomly oriented asymmetric UNC-40 localization and a wandering axon phenotype. With UNC-6, there is normal UNC-40 localization and axon migration. A single UNC-6 amino acid substitution enhances the mutant phenotypes, whereas UNC-6 second-site amino acid substitutions suppress the phenotypes. We propose that UNC-40 mediates multiple signals to polarize and orient asymmetry. One signal triggers the intrinsic ability of HSN to polarize and causes randomly oriented asymmetry. Concurrently, another signal biases the orientation of the asymmetry relative to the UNC-6 gradient. The UNC-40 ectodomain mutation activates the polarization signal, whereas different forms of the UNC-6 ligand produce UNC-40 conformational changes that allow or prohibit the orientation signal.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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The Roles of Multiple UNC-40 (DCC) Receptor-Mediated Signals in Determining Neuronal Asymmetry Induced by the UNC-6 (Netrin) Ligand

Xu¹,

Li²,

Wadsworth³

2009

Genetics

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“…Further study will be required whether the Lpd-mediated actin-based cytoskeletal regulation system is also involved in Sema4D-mediated axonal growth cone collapse. A recent report has shown that Mig-10, a C. elegans Lpd ortholog, interacts with active Rac, a Rho family protein, and Mig-10 regulates axon guidance downstream of Rac in response to netrin and slit (Quinn et al, 2008). The Plexin-B subfamily has been shown to bind to Rac and inhibit its signaling (Hu et al, 2001;Vikis et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Semaphorin 4D/Plexin-B1-Mediated M-Ras GAP Activity Regulates Actin-Based Dendrite Remodeling through Lamellipodin

Tasaka

Negishi²,

Oinuma³

2012

Journal of Neuroscience

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Semaphorins have been identified as repulsive guidance molecules in the developing nervous system. We recently reported that the semaphorin 4D (Sema4D) receptor Plexin-B1 induces repulsion in axon and dendrites by functioning as a GTPase-activating protein (GAP) for R-Ras and M-Ras, respectively. In axons, Sema4D stimulation induces growth cone collapse, and downregulation of R-Ras activity by Plexin-B1-mediated GAP activity is required for the action. Axonal R-Ras GAP activity downregulates phosphatidylinositol 3-kinase signaling pathway, and thereby induces inactivation of a microtubule assembly promoter protein, CRMP-2. However, in contrast to the well studied roles of semaphorins and plexins in axonal guidance, signaling molecules linking M-Ras GAP to dendritic cytoskeleton remain obscure. Here we identified an Ena/VASP ligand, Lamellipodin (Lpd), as a novel effector of M-Ras in dendrites. Lpd was expressed in F-actin-rich distal dendritic processes and was required for both basal and M-Ras-mediated dendrite development. Subcellular fractionation showed M-Ras-dependent membrane translocation of Lpd, which was suppressed by Sema4D. Furthermore, the Ena/VASP-binding region within Lpd was required for dendrite development, and its membrane targeting was sufficient to overcome the Sema4D-mediated reduction of dendritic outgrowth and disappearance of F-actin from distal dendrites. Furthermore, in utero electroporation experiments also indicated that regulation of the M-Ras-Lpd system by the GAP activity of Plexin is involved in the normal development of cortical dendrites in vivo. Overall, our study sheds light on how repulsive guidance molecules regulate actin cytoskeleton in dendrites, revealing a novel mechanism that the M-Ras-Lpd system regulates actin-based dendrite remodeling by Sema/Plexin in rats or mice of either sex.

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Activation of ADF/cofilin mediates attractive growth cone turning toward nerve growth factor and netrin‐1

Marsick

Flynn

Santiago-Medina

et al. 2010

Developmental Neurobiology

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Proper neural circuitry requires that growth cones, motile tips of extending axons, respond to molecular guidance cues expressed in the developing organism. However, it is unclear how guidance cues modify the cytoskeleton to guide growth cone pathfinding. Here we show acute treatment with two attractive guidance cues, nerve growth factor (NGF) and netrin-1, for embryonic dorsal root ganglion and temporal retinal neurons, respectively, results in increased growth cone membrane protrusion, actin polymerization, and filamentous actin (F-actin). ADF/cofilin (AC) family proteins facilitate F-actin dynamics, and we found the inactive phosphorylated form of AC is decreased in NGF- or netrin-1-treated growth cones. Directly increasing AC activity mimics addition of NGF or netrin-1 to increase growth cone protrusion and F-actin levels. Extracellular gradients of NGF, netrin-1, and a cell-permeable AC elicit attractive growth cone turning and increased F-actin barbed ends, F-actin accumulation, and active AC in growth cone regions proximal to the gradient source. Reducing AC activity blunts turning responses to NGF and netrin. Our results suggest that gradients of NGF and netrin-1 locally activate AC to promote actin polymerization and subsequent growth cone turning toward the side containing higher AC activity.

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CED-10/Rac1 Mediates Axon Guidance by Regulating the Asymmetric Distribution of MIG-10/Lamellipodin

Cited by 71 publications

References 30 publications

The Roles of Multiple UNC-40 (DCC) Receptor-Mediated Signals in Determining Neuronal Asymmetry Induced by the UNC-6 (Netrin) Ligand

The Roles of Multiple UNC-40 (DCC) Receptor-Mediated Signals in Determining Neuronal Asymmetry Induced by the UNC-6 (Netrin) Ligand

Semaphorin 4D/Plexin-B1-Mediated M-Ras GAP Activity Regulates Actin-Based Dendrite Remodeling through Lamellipodin

Activation of ADF/cofilin mediates attractive growth cone turning toward nerve growth factor and netrin‐1

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