Rac1 and RhoA Promote Neurite Outgrowth through Formation and Stabilization of Growth Cone Point Contacts

Woo, Stephanie; Gómez, Timothy M.

doi:10.1523/jneurosci.4209-05.2006

Cited by 171 publications

(211 citation statements)

References 57 publications

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“…Our data allow us to speculate that, in tau depleted growth cones, the observed effects may have involved a decrease in activated Src that led to a decrease in Rac activity and the ability of the cell to establish or maintain lamellipodia. In agreement, local inactivation of SFKs also resulted in growth cone collapse (Robles et al, 2005) and growth cones expressing dominant negative Rac1 had reduced lamellipodial protrusions (Woo and Gomez, 2006). Most recently, in PC12 cells, tau has been localized to lamellipodia-like structures in an NGF-dependent manner, where it associated with actin (Yu and Rasenick, 2006).…”

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confidence: 53%

Tau impacts on growth-factor-stimulated actin remodeling

Sharma

Litersky

Bhaskar

et al. 2007

Journal of Cell Science

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The microtubule-associated protein tau interacts with the SH3 domain of non-receptor Src family protein tyrosine kinases. A potential consequence of the SH3 interaction is the upregulation of tyrosine kinase activity. Here we investigated the activation of Src or Fyn by tau, both in vitro and in vivo. Tau increased the kinase activity in in vitro assays and in transfected COS7 cells. In plateletderived growth factor (PDGF)-stimulated fibroblasts, tau appeared to prime Src for activation following PDGF stimulation, as reflected by changes in Src-mediated actin rearrangements. In addition, while fibroblasts normally recovered actin stress fibers by 5-7 hours after PDGF stimulation, tau-expressing cells showed sustained actin breakdown. Microtubule association by tau was not required for the observed changes in actin morphology. Inhibition of Src kinases or a mutant deficient in Src interaction reduced the effects, implicating Src family protein tyrosine kinases as a mediator of the effects of tau on actin rearrangements. Our results provide evidence that the interaction of tau with Src upregulates tyrosine kinase activity and that this interaction allows tau to impact on growth-factor-induced actin remodeling. Journal of Cell Science Tau impacts on actin remodeling Results Tau affects SFK activityWe have previously shown through in vitro binding assays that human tau interacted with the SH3 domain of Fyn and Src (Bhaskar et al., 2005;Lee et al., 1998). Based on the crystal structure of Src, SH3 ligands are thought to 'unclamp' an inactive form of Src, enhancing its activation (Xu et al., 1999;Xu et al., 1997). Our first indication that tau might function in this manner came from experiments initially performed to examine the ability of tyrosine-phosphorylated tau to associate with microtubules. Purified tau and Fyn were incubated in an in vitro kinase reaction to first generate tyrosinephosphorylated tau. The reaction was then added to taxolstabilized microtubules. Upon examining the microtubule pellet for tyrosine-phosphorylated tau, we discovered that the taxol-stabilized tubulin was also tyrosine phosphorylated, presumably by the Fyn that had been carried over from the kinase reaction. Moreover, although Fyn alone was capable of phosphorylating taxol-stabilized microtubules, the presence of tau greatly enhanced the phosphorylation (Fig. 1A, compare lanes 4 and 8).However, because tau binds to microtubules, a possible explanation for the enhanced tubulin phosphorylation was that tau was simply bringing Fyn to the microtubules and facilitating tubulin phosphorylation without affecting Fyn activity. This would predict that a fragment of tau lacking microtubule-binding activity would be incapable of enhancing the phosphorylation. We therefore tested an N-terminal fragment of tau that binds to Fyn SH3 but lacks the microtubule-binding repeats [amino acids 1-184 (Lee et al., 1998)]. By using the same protocol in which the tau fragment was incubated with Fyn and then added to taxol-stabilized microtubules, we found ...

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confidence: 53%

Tau impacts on growth-factor-stimulated actin remodeling

Sharma

Litersky

Bhaskar

et al. 2007

Journal of Cell Science

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“…The Sema 3A response involves multiple mechanisms, including the disruption of the actin cytoskeletal and focal complexes (Fan et al, 1993;Fritsche et al, 1999;Woo and Gomez, 2006). Collapse of COS-7 cells coexpressing Plexin-A1 and NP-1 does not seem to involve contractile responses (Turner et al, 2004); however, retraction of DRG neurons does involve myosin II (Gallo, 2006).…”

Section: Drg Growth Cones Contain All Three Isoforms (Iia Iib and Imentioning

confidence: 99%

“…Collapse is destabilization and loss of peripheral actin rich lamellipodia and filopodia that contain and can be stabilized by myosin IIA. These regions are also known to be associated with focal contacts in neuroblastoma cells (Wylie and Chantler, 2001), and focal complexes in growth cones from Xenopus spinal neurons can be destabilized by Sema 3A treatment potentially leading to decreased adhesion (Woo and Gomez, 2006). Collapse also leads to redistribution and reorganization of actin to bundles within the neurite (Gallo, 2006) close or overlapping with regions where myosin IIB concentrates.…”

Section: Cytoskeletal Dependence Of Sema 3a-induced Retractionmentioning

confidence: 99%

“…The Sema 3A-dependent repulsive response is associated with growth cone collapse and is known to involve the Rho family of small GTPases that act as molecular switches (Jin and Strittmatter, 1997;Kuhn et al, 1999;Turner et al, 2004) and their downstream effectors, the actin cytoskeleton and focal contacts (Fan et al, 1993;Fritsche et al, 1999;Woo and Gomez, 2006). However the pathways that are involved and their relationship to growth cone responses has not been fully characterized.…”

Section: Introductionmentioning

confidence: 99%

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Dorsal Root Ganglion Neurons React to Semaphorin 3A Application through a Biphasic Response that Requires Multiple Myosin II Isoforms

Brown

Wysolmerski

Bridgman

2009

MBoC

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Growth cone responses to guidance cues provide the basis for neuronal pathfinding. Although many cues have been identified, less is known about how signals are translated into the cytoskeletal rearrangements that steer directional changes during pathfinding. Here we show that the response of dorsal root ganglion (DRG) neurons to Semaphorin 3A gradients can be divided into two steps: growth cone collapse and retraction. Collapse is inhibited by overexpression of myosin IIA or growth on high substrate-bound laminin-1. Inhibition of collapse also prevents retractions; however collapse can occur without retraction. Inhibition of myosin II activity with blebbistatin or by using neurons from myosin IIB knockouts inhibits retraction. Collapse is associated with movement of myosin IIA from the growth cone to the neurite. Myosin IIB redistributes from a broad distribution to the rear of the growth cone and neck of the connecting neurite. High substrate-bound laminin-1 prevents or reverses these changes. This suggests a model for the Sema 3A response that involves loss of growth cone myosin IIA to facilitate actin meshwork instability and collapse, followed by myosin IIB concentration at the rear of the cone and neck region where it associates with actin bundles to drive retraction. INTRODUCTIONCorrect responses to extracellular signaling molecules during development are essential for the formation of the mammalian central and peripheral nervous systems (Sobeih and Corfas, 2002;Hagg, 2005). Growth cones navigate through the tissue environment in vivo by integrating growth-promoting signals with guidance cue signals at choice points and then responding through two opposing processes: extension and retraction (Buettner, 1994;Dontchev and Letourneau, 2003). This steers the growing axon to the correct target location. Cues are classified as either attractive or repulsive depending on their ability to invoke responses. In vitro attractants generally stimulate growth and turning toward the source of the cue, whereas repulsive cues induce turning away from the cue (Lohof et al., 1992;Fan and Raper, 1995). Repulsive cues can also cause growth cone collapse and temporary cessation of outgrowth (Luo et al., 1993;Wahl et al., 2000). It is unclear to what degree full or partial collapse or even retractions are associated with growth cone steering in vivo (Knobel et al., 1999;Mason and Erskine, 2000;Kalil et al., 2000). The complex in vivo environment is likely to result in a variety of behaviors that reflect the integration of signals from multiple cues within a short time period. Some of these interactions occur at the receptor level (Stein and Tessier-Lavigne, 2001;Halloran and Wolman, 2006), but others may converge on common growth cone effector mechanisms. To understand growth cone behavior responsible for pathfinding in vivo, it is important to fully dissect the responses to individual cues in vitro.Sema 3A is secreted by cells in the developing spinal cord and repels dorsal root ganglion (DRG) neurons that are sensitive to nerv...

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“…Extracellular nano/microtopography signals are locally retrieved through a complex phenomenon called contact guidance and can drive many neuronal activities, such as differentiation, polarization, neurite pathfinding, nucleokinesis and the final CNS wiring [10][11][12][13][14][15][16]. These processes are tightly regulated and involve coordinated interactions between microtubules and the actin cytoskeleton [16,17] as well as the establishment and maturation of focal adhesions (FAs) [18]. In particular, growth cones (GCs)-dynamic structures rich in actin filaments at the tips of neurites-move by probing environmental cues by filopodia [13,19,20] and integrating multiple sources of physico-chemical information.…”

Section: Introductionmentioning

confidence: 99%

Interaction of leech neurons with topographical gratings: comparison with rodent and human neuronal lines and primary cells

et al. 2014

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Controlling and improving neuronal cell migration and neurite outgrowth are critical elements of tissue engineering applications and development of artificial neuronal interfaces. To this end, a promising approach exploits nano/microstructured surfaces, which have been demonstrated to be capable of tuning neuronal differentiation, polarity, migration and neurite orientation. Here, we investigate the neurite contact guidance of leech neurons on plastic gratings (GRs; anisotropic topographies composed of alternating lines of grooves and ridges). By high-resolution microscopy, we quantitatively evaluate the changes in tubulin cytoskeleton organization and cell morphology and in the neurite and growth cone development. The topography-reading process of leech neurons on GRs is mediated by filopodia and is more responsive to 4-µm-period GRs than to smaller period GRs. Leech neuron behaviour on GRs is finally compared and validated with several other neuronal cells, from murine differentiated embryonic stem cells and primary hippocampal neurons to differentiated human neuroblastoma cells.

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Rac1 and RhoA Promote Neurite Outgrowth through Formation and Stabilization of Growth Cone Point Contacts

Cited by 171 publications

References 57 publications

Tau impacts on growth-factor-stimulated actin remodeling

Tau impacts on growth-factor-stimulated actin remodeling

Dorsal Root Ganglion Neurons React to Semaphorin 3A Application through a Biphasic Response that Requires Multiple Myosin II Isoforms

Interaction of leech neurons with topographical gratings: comparison with rodent and human neuronal lines and primary cells

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