Role of phosphatidylinositol 3‐kinase in neuronal survival and axonal outgrowth of adult mouse dorsal root ganglia explants

Abstract

Adult ganglionic peripheral neurons have lost dependence on target-derived neurotrophin signaling for survival and regeneration after injury. To understand the mechanisms required to sustain such processes at maturity, we are studying neuronal survival and axonal outgrowth of adult mouse dorsal root ganglia (DRG) explants. We have here examined the role of phosphatidylinositol 3-kinase (PI3-K) activity. Both neuronal survival and axonal outgrowth of spontaneously growing preparations were decreased significantly by the PI3-K inhibitor LY294002 as was the increased outgrowth caused by nerve growth factor or glial cell line-derived factor. Inhibition of PI3-K activity promoted neuronal cell death to the same extent in the presence as in the absence of a growth factor, whereas inhibition of mitogen-activated protein kinase, MAPK, lacked effect. Using a compartmentalized system, it could be shown that only axonal outgrowth was decreased when the outgrowth region only was exposed to LY294002. Already-formed growth cones showed morphological changes within 5-10 min after exposure to LY294002. Akt (PKB) is one downstream effector of PI3-K. Immunofluorescence revealed the presence of activated Akt in DRG cell bodies and in axonal growth cones. Immunoreactivity was decreased by PI3-K inhibition. The results suggest that Akt is constitutively active in adult DRG neurons, and that PI3-K mediated processes are involved in neuronal survival of one or more DRG neuronal subpopulations and also in axonal elongation. The possible significance of Akt signaling for these effects is discussed.

Expression of p-Akt in Sensory Neurons and Spinal Cord after Peripheral Nerve Injury

“…Pezet et al [25] reported that very low p-Akt levels were present in 'almost all neurons' in the rat. This is in agreement with the in vitro study in the mouse by Edström and Ekström [58] , reporting that most neurons from freshly dissected DRGs are p-Akt-IR, whereas other cell types, such as satellite cells, were negative. Zhuang et al [24] and Xu et al [26] found that ϳ 10% of rat DRG neurons are pAkt positive, versus our 50% in the mouse.…”

“…Our findings also seem to contrast the marked decrease in pAkt after 24 h in mouse DRG cultures, where all neurons, of course, have been axotomized, an effect which, however, was recorded very early, just after 24 h in culture [58] . So the differences could be explained by different experimental models and/or species differences.…”

“…Several studies have been published on localization, expression and regulation of Akt/phosphorylated Akt (pAkt) in DRG neurons and spinal cord of the rat [24][25][26][27]57] , but with regard to the mouse there are only two reports, one in vitro study [58] and one report focused on spinal motor neurons in vivo [57] . The aim of the present study is therefore to quantitatively and qualitatively investigate, in the mouse and in vivo with immunohistochemistry, p-Akt in DRG neurons and spinal cord after sciatic nerve transection and after peripheral inflammation induced by intradermal injection of carrageenan.…”

PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis

“…Activated Akt is released from the cell membrane into the cytoplasm or nucleus to further transmit the signals and execute its biological functions. Thus, Akt phosphorylation can be used as an indicator of PI3K activity [10,11].…”

Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade

“…PI3-kinase has been shown to be involved in neurite outgrowth signaling (Rodgers and Theibert, 2002), especially in axonal formation (Edström and Ekström, 2003;Ménager et al, 2004). On the other hand, teneurin-2 is a type II transmembrane protein (Otaki and Firestein, 1999), and is involved in the formation of filopodia, and growth cone enlargement (Rubin et al, 1999).…”