title: TrkA mediates retrograde semaphorin 3A signaling through plexin A4 to regulate dendritic branching.
abstract: Semaphorin 3A (Sema3A), a secretory semaphorin, exerts various biological actions through a complex between neuropilin-1 and plexin-As (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2 (also known as GRIA2), an AMPA receptor subunit. Here, we investigated a possible interaction between retrograde signaling pathways for Sema3A and nerve growth factor (NGF). Sema3A induces colocalization of PlexA4 (also known as PLXNA4) signals with those of tropomyosin-related kinase A (TrkA, also known as NTRK1) in growth cones, and these colocalized signals were then observed along the axons. The time-lapse imaging of PlexA4 and several TrkA mutants showed that the kinase and dynein-binding activity of TrkA were required for Sema3A-induced retrograde transport of the PlexA4-TrkA complex along the axons. The inhibition of the phosphoinositide 3-kinase (PI3K)-Akt signal, a downstream signaling pathway of TrkA, in the distal axon suppressed Sema3A-induced dendritic localization of GluA2. The knockdown of TrkA suppressed Sema3A-induced dendritic localization of GluA2 and that suppressed Sema3A-regulated dendritic branching both in vitro and in vivo These findings suggest that by interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning.
authors.affiliation: Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA goshima@med.yokohama-cu.ac.jp ynaoya-ycu@umin.net.
authors.forename: Naoya
authors.identifier: 0000-0001-7667-5264
authors.initials: N
authors.lastname: Yamashita
authors.affiliation: Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamane
authors.affiliation: National Center of Neurology and Psychiatry, National Institute of Neuroscience, Department of Ultrastructural Research, 4-1-1, Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Suto
authors.affiliation: Department of Molecular Pharmacology and Neurobiology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan goshima@med.yokohama-cu.ac.jp ynaoya-ycu@umin.net.
authors.forename: Yoshio
authors.identifier: 0000-0002-1944-7051
authors.initials: Y
authors.lastname: Goshima
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000235:genetics / Q000378:metabolism*; D002645:Chickens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020439:Growth Cones / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D030161:Avian Proteins; D009419:Nerve Tissue Proteins; C492110:Plxna4 protein, mouse; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020917:Receptor, trkA; D051057:Proto-Oncogene Proteins c-akt
keywords: Axonal transport; Hippocampus; NGF; PlexA4; Semaphorin 3A; TrkA