Group IVA phospholipase A₂ is necessary for growth cone repulsion and collapse

Abstract

The repellent semaphorin 3A (Sema3A) causes growth cone turning or collapse by triggering cytoskeletal rearrangements and detachment of adhesion sites. Growth cone detachment is dependent on eicosanoid activation of protein kinase C epsilon (PKCε), but the characterization of the phospholipase A2 (PLA2) that releases arachidonic acid (AA) for eicosanoid synthesis has remained elusive. Here we show in rat dorsal root ganglion neurons that Sema3A stimulates PLA2 activity, that Sema3A-induced growth cone turning and collapse are dependent on the release of AA, and that the primary PLA2 involved is the Group IV α isoform (GIVA). Silencing GIVA expression renders growth cones resistant to Sema3A-induced collapse, and GIVA inhibition reverses Sema3A-induced repulsion into attraction. These studies identify a novel, early step in Sema3A-signaling and a PLA2 necessary for growth cone repulsion and collapse.

Inhibition of Cytosolic Phospholipase A2Has Neuroprotective Effects on Motoneuron and Muscle Atrophy after Spinal Cord Injury

“…The other possibility is that cPLA 2 may have a direct effect on dendrites. Such a direct effect is supported by other reports that cPLA 2 activation mediates Sema3A-induced growth cone collapse 16,17 , suggesting that cPLA 2 activation could be directly involved in dendritic retraction after SCI. The attenuation in dendritic atrophy we observed in ATK-treated animals could potentially maintain motor activation and account for the protective effects of ATK on locomotor function we have observed 13 .…”

“…Of these, cPLA 2 is the most important PLA 2 isozyme, and has been implicated as an effector in receptor-mediated release of arachidonic acid (AA) and exhibits strong preference for deacylation of AA over other fatty acids 9,15 . Because cPLA 2 activation mediates Sema3A-induced growth cone collapse 16,17 , it is possible that cPLA 2 activation is involved in dendritic atrophy after SCI. However, no studies to date have examined whether cPLA 2 has a role in motoneuron atrophy.…”

Role of Cytosolic Phospholipase A2 in Oxidative and Inflammatory Signaling Pathways in Different Cell Types in the Central Nervous System

“…There is evidence for cPLA 2 to modulate vesicle formation, for promoting neurite outgrowth and maintenance of growth cone activity. In the dorsal root ganglion, Semaphorin 3A (a class of secreted and membrane protein) can trigger a signaling pathway involving cPLA 2 activation, AA release and synthesis of 12(S)-hydroxyeicosatetraenoic acid (12(S) HETE), and in turn, mediates neuronal growth cone activity [44]. In agreement with the role of cPLA 2 in neuronal membrane and synaptic activity, hippocampal neurons isolated from cPLA 2 knockout (KO) mice showed measurable differences in the nuclei and soma volume, and structure of the synaptic cleft as compared with neurons from wild-type animals [45].…”

Integrating Cytosolic Phospholipase A2 with Oxidative/Nitrosative Signaling Pathways in Neurons: A Novel Therapeutic Strategy for AD

“…In support of the role of cPLA 2 in mediating the toxic events of Aβ, neurons isolated from mice deficient in cPLA 2 −/− showed resistance to the toxic effects of Aβ (Desbene et al 2011). Besides the response to cell injury, cPLA 2 was shown to play an important role in mediating neuronal homeostatic processes related to growth cone repulsion and collapse, and neurite outgrowth and differentiation during neuro-development (Schaeffer et al 2009, Sanford et al 2012). In an in vivo study, intracerebroventricular injection of Aβ oligomer to wild type mice caused activation of cPLA 2 , which in turn led to a decline in cognitive function and reduction of synaptic markers (Desbene et al 2011).…”