Growth Cone Collapse Induced by Semaphorin 3A Requires 12/15-Lipoxygenase

Mikule, Keith; Gatlin, Jesse C.; Houssaye, Becky A. de la; Pfenninger, Karl H.

doi:10.1523/jneurosci.22-12-04932.2002

Cited by 61 publications

(80 citation statements)

References 41 publications

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“…It increases growth cone levels of AA and of 12-and 15-HETE and also causes growth cone detachment. These repellent effects have been established for semaphorin 3A as well (6). The present studies investigate subsequent signaling steps.…”

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confidence: 69%

“…Thrombin-induced Growth Cone Collapse-We have demonstrated elsewhere that (a) thrombin induces growth cone collapse, (b) thrombin increases the intracellular level of 12(S)-HETE, and (c) 12(S)-HETE is necessary and sufficient for collapse (5,6). Here we show that both thrombin and 12(S)-HETE directly activate PKC⑀ (Figs.…”

Section: Resultsmentioning

confidence: 99%

“…Growth cones guide neurites to predetermined targets by either turning toward or away from attractive or repulsive pathfinding cues, respectively (1,2). Growth cone repulsion is the result not only of cytoskeletal rearrangements but also of detachment from the growth substratum (3)(4)(5)(6), suggesting that adhesion sites may be targets of the signaling mechanism involved. Results from our laboratory describe elements of a repellent-activated signaling pathway that causes growth cone detachment and collapse (5,6).…”

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confidence: 99%

“…Growth cone repulsion is the result not only of cytoskeletal rearrangements but also of detachment from the growth substratum (3)(4)(5)(6), suggesting that adhesion sites may be targets of the signaling mechanism involved. Results from our laboratory describe elements of a repellent-activated signaling pathway that causes growth cone detachment and collapse (5,6). Stimulation of this pathway by thrombin or semaphorin 3A results in the synthesis of 12(S)-and 15(S)-hydroxyeicosatetraenoic acid (HETE) 1 from arachidonic acid (AA).…”

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confidence: 99%

“…This is catalyzed by leukocyte 12/15-lipoxygenase (12/15-LO) (7). 12(S)-HETE is necessary and sufficient for collapse of cortical or dorsal-rootganglion growth cones as well as for the retraction of cancer cell pseudopods (5,6,8). A question of significant interest concerns the mechanism by which 12(S)-HETE causes detachment and collapse.…”

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Eicosanoid Activation of Protein Kinase C ϵ

Mikule

Sunpaweravong

Gatlin

et al. 2003

Journal of Biological Chemistry

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Exposure of growing neurons to thrombin or semaphorin 3A stimulates a receptor-mediated signaling cascade that results in collapse of their growth cones. This collapse response necessitates eicosanoid production, as we have shown earlier. The present report investigates whether and which protein kinase C (PKC) isoforms may be activated by such eicosanoids. To examine these questions, we isolated growth cones from fetal rat brain and tested whether thrombin or the eicosanoid, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), could activate endogenous growth cone PKC. We show that both thrombin and 12(S)-HETE stimulate the phosphorylation of the myristoylated alanine-rich protein kinase C substrate, an 87-kDa adhesion site protein. Furthermore, we show both with immunoprecipitated and with recombinant PKC that 12(S)-HETE activation is selective for the ⑀ isoform and does not require accessory proteins. Last, we demonstrate that PKC activation is necessary for thrombin-induced growth cone collapse. These data indicate that eicosanoid-mediated repellent effects result from the direct and selective activation of PKC⑀ and suggest the involvement of myristoylated alanine-rich protein kinase C substrate phosphorylation in growth cone collapse.

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Eicosanoid Activation of Protein Kinase C ϵ

Mikule

Sunpaweravong

Gatlin

et al. 2003

Journal of Biological Chemistry

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PLA₂ and secondary metabolites of arachidonic acid control filopodial behavior in neuronal growth cones

Geddis

Tornieri

Giesecke

et al. 2003

Cell Motil. Cytoskeleton

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The neuronal growth cone provides the sensory and motor structure that guides neuronal processes to their target. The ability of a growth cone to navigate correctly depends on its filopodia, which sample the environment by continually extending and retracting as the growth cone advances. Several second messengers systems that are activated upon contact with extracellular cues have been reported to affect growth cone morphology by changing the length and number of filopodia. Because recent studies have suggested that guidance cues can signal via G-protein coupled receptors to regulate phospholipases, we here investigated whether phospholipase A2 (PLA2) may control filopodial dynamics and could thereby affect neuronal pathfinding. Employing identified Helisoma neurons in vitro, we demonstrate that inhibition of PLA2 with 2 microM BPB caused a 40.3% increase in average filopodial length, as well as a 37.3% reduction in the number of filopodia on a growth cone. The effect of PLA2 inhibition on filopodial length was mimicked by the inhibition of G-proteins with 500 ng/ml pertussis toxin and was partially blocked by the simultaneous activation of PLA2 with 50 nM melittin. We provide evidence that PLA2 acts via production of arachidonic acid (AA), because (1) the effect of inhibition of PLA2 could be counteracted by supplying AA exogenously, and (2) the inhibition of cyclooxygenase, which metabolizes AA into prostaglandins, also increased filopodial length. We conclude that filopodial contact with extracellular signals that alter the activity of PLA2 can control growth cone morphology and may affect neuronal pathfinding by regulating the sensory radius of navigating growth cones.

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Extracellular inhibitors, repellents, and semaphorin/plexin/MICAL‐mediated actin filament disassembly

2011

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Multiple extracellular signals have been identified that regulate actin dynamics within motile cells, but how these instructive cues present on the cell surface exert their precise effects on the internal actin cytoskeleton is still poorly understood. One particularly interesting class of these cues is a group of extracellular proteins that negatively alter the movement of cells and their processes. Over the years, these types of events have been described using a variety of terms and herein we provide an overview of inhibitory/repulsive cellular phenomena and highlight the largest known protein family of repulsive extracellular cues, the Semaphorins. Specifically, the Semaphorins (Semas) utilize Plexin cell-surface receptors to dramatically collapse the actin cytoskeleton and we summarize what is known of the direct molecular and biochemical mechanisms of Sema-triggered actin filament (F-actin) disassembly. We also discuss new observations from our lab that reveal that the multi-domain oxidoreductase (Redox) enzyme MICAL, an important mediator of Sema/Plexin repulsion, is a novel F-actin disassembly factor. Our results indicate that MICAL triggers Sema/Plexin-mediated reorganization of the F-actin cytoskeleton and suggest a role for specific Redox signaling events in regulating actin dynamics.

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Growth Cone Collapse Induced by Semaphorin 3A Requires 12/15-Lipoxygenase

Cited by 61 publications

References 41 publications

Eicosanoid Activation of Protein Kinase C ϵ

Eicosanoid Activation of Protein Kinase C ϵ

PLA₂ and secondary metabolites of arachidonic acid control filopodial behavior in neuronal growth cones

Extracellular inhibitors, repellents, and semaphorin/plexin/MICAL‐mediated actin filament disassembly

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Growth Cone Collapse Induced by Semaphorin 3A Requires 12/15-Lipoxygenase

Cited by 61 publications

References 41 publications

Eicosanoid Activation of Protein Kinase C ϵ

Eicosanoid Activation of Protein Kinase C ϵ

PLA2 and secondary metabolites of arachidonic acid control filopodial behavior in neuronal growth cones

Extracellular inhibitors, repellents, and semaphorin/plexin/MICAL‐mediated actin filament disassembly

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PLA₂ and secondary metabolites of arachidonic acid control filopodial behavior in neuronal growth cones