title: Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization.
abstract: BACKGROUND
  Wnt5a, originally identified as a guidance cue for commissural axons, activates a non-canonical pathway critical for cortical axonal morphogenesis. The molecular signaling cascade underlying this event remains obscure.
  
  
  RESULTS
  Through Ca(2+) imaging in acute embryonic cortical slices, we tested if radially migrating cortical excitatory neurons that already bore primitive axons were sensitive to Wnt5a. While Wnt5a only evoked brief Ca(2+) transients in immature neurons present in the intermediate zone (IZ), Wnt5a-induced Ca(2+) oscillations were sustained in neurons that migrated out to the cortical plate (CP). We wondered whether this early Wnt5a-Ca(2+) signaling during neuronal polarization has a morphogenetic consequence. During transition from round to polarized shape, Wnt5a administration to immature cultured cortical neurons specifically promoted axonal, but not dendritic, outgrowth. Pharmacological and genetic inhibition of the CaMKK-CaMKIα pathway abolished Wnt5a-induced axonal elongation, and rescue of CaMKIα in CaMKIα-knockdown neurons restored Wnt5a-mediated axon outgrowth.
  
  
  CONCLUSIONS
  This study suggests that Wnt5a activates Ca(2+) signaling during a neuronal morphogenetic time window when axon outgrowth is critically facilitated. Furthermore, the CaMKK-CaMKIα cascade is required for the axonal growth effect of Wnt5a during neuronal polarization.
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. horigane@m.u-tokyo.ac.jp.|Department of Neuroscience I, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan. horigane@m.u-tokyo.ac.jp.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Horigane
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. ageta-ishihara.natsumi@h.mbox.nagoya-u.ac.jp.|Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Furo-cho, Chikusa, Nagoya, 464-8602, Japan. ageta-ishihara.natsumi@h.mbox.nagoya-u.ac.jp.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Ageta-Ishihara
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. kamijo@m.u-tokyo.ac.jp.|CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan. kamijo@m.u-tokyo.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kamijo
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. hajime@m.u-tokyo.ac.jp.|CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan. hajime@m.u-tokyo.ac.jp.
authors.forename: Hajime
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. michiko@m.u-tokyo.ac.jp.
authors.forename: Michiko
authors.initials: M
authors.lastname: Okamura
authors.affiliation: Department of Molecular Biology, Division of Biological Sciences, Nagoya University Graduate School of Science, Furo-cho, Chikusa, Nagoya, 464-8602, Japan. kinoshita.makoto@c.mbox.nagoya-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. stakemoto@riem.nagoya-u.ac.jp.|Department of Neuroscience I, Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan. stakemoto@riem.nagoya-u.ac.jp.|PRESTO, Japan Science and Technology Agency, Chiyoda-ku, Tokyo, 102-0076, Japan. stakemoto@riem.nagoya-u.ac.jp.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Takemoto-Kimura
authors.affiliation: Department of Neurochemistry, Graduate School of Medicine, The University of Tokyo, Igakubu-3-gokan, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. hbito@m.u-tokyo.ac.jp.|CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan. hbito@m.u-tokyo.ac.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Bito
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism*; D002454:Cell Differentiation; D002465:Cell Movement; D016764:Cell Polarity; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003712:Dendrites / Q000378:metabolism; D005260:Female; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009024:Morphogenesis; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1