title: Asymmetric PI(3,4,5)P3 and Akt signaling mediates chemotaxis of axonal growth cones.
abstract: The action of many extracellular guidance cues on axon pathfinding requires Ca2+ influx at the growth cone (Hong et al., 2000; Nishiyama et al., 2003; Henley and Poo, 2004), but how activation of guidance cue receptors leads to opening of plasmalemmal ion channels remains largely unknown. Analogous to the chemotaxis of amoeboid cells (Parent et al., 1998; Servant et al., 2000), we found that a gradient of chemoattractant triggered rapid asymmetric PI(3,4,5)P3 accumulation at the growth cone's leading edge, as detected by the translocation of a GFP-tagged binding domain of Akt in Xenopus laevis spinal neurons. Growth cone chemoattraction required PI(3,4,5)P3 production and Akt activation, and genetic perturbation of polarized Akt activity disrupted axon pathfinding in vitro and in vivo. Furthermore, patch-clamp recording from growth cones revealed that exogenous PI(3,4,5)P3 rapidly activated TRP (transient receptor potential) channels, and asymmetrically applied PI(3,4,5)P3 was sufficient to induce chemoattractive growth cone turning in a manner that required downstream Ca2+ signaling. Thus, asymmetric PI(3,4,5)P3 elevation and Akt activation are early events in growth cone chemotaxis that link receptor activation to TRP channel opening and Ca2+ signaling. Altogether, our findings reveal that PI(3,4,5)P3 elevation polarizes to the growth cone's leading edge and can serve as an early regulator during chemotactic guidance.
authors.affiliation: Mayo Graduate School, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Henle
authors.forename: Gordon
authors.initials: G
authors.lastname: Wang
authors.forename: Ellen
authors.initials: E
authors.lastname: Liang
authors.forename: May
authors.initials: M
authors.lastname: Wu
authors.forename: Mu-Ming
authors.initials: MM
authors.lastname: Poo
authors.forename: John R
authors.initials: JR
authors.lastname: Henley
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010716:Phosphatidylinositols / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018709:Statistics, Nonparametric; D050052:TRPC Cation Channels / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D010716:Phosphatidylinositols; D050052:TRPC Cation Channels; C118303:phosphoinositide-3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium