title: The Core Molecular Machinery Used for Engulfment of Apoptotic Cells Regulates the JNK Pathway Mediating Axon Regeneration in Caenorhabditis elegans.
abstract: The mechanisms that govern the ability of specific neurons to regenerate their axons after injury are not well understood. In Caenorhabditis elegans, the initiation of axon regeneration is positively regulated by the JNK-MAPK pathway. In this study, we identify two components functioning upstream of the JNK pathway: the Ste20-related protein kinase MAX-2 and the Rac-type GTPase CED-10. CED-10, when bound by GTP, interacts with MAX-2 and functions as its upstream regulator in axon regeneration. CED-10, in turn, is activated by axon injury via signals initiated from the integrin α-subunit INA-1 and the nonreceptor tyrosine kinase SRC-1 and transmitted via the signaling module CED-2/CrkII-CED-5/Dock180-CED-12/ELMO. This module is also known to regulate the engulfment of apoptotic cells during development. Our findings thus reveal that the molecular machinery used for engulfment of apoptotic cells also promotes axon regeneration through activation of the JNK pathway.
  
  
  
  The molecular mechanisms of axon regeneration after injury remain poorly understood. In Caenorhabditis elegans, the initiation of axon regeneration is positively regulated by the JNK-MAPK pathway. In this study, we show that integrin, Rac-GTPase, and several other molecules, all of which are known to regulate engulfment of apoptotic cells during development, also regulate axon regeneration. This signaling module activates the JNK-MAPK cascade via MAX-2, a PAK-like protein kinase that binds Rac. Our findings thus reveal that the molecular machinery used for engulfment of apoptotic cells also promotes axon regeneration through activation of the JNK pathway.
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Strahil Iv
authors.initials: SI
authors.lastname: Pastuhov
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Fujiki
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsuge
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Asai
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hirose
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan g44177a@nucc.cc.nagoya-u.ac.jp i45556a@cc.nagoya-u.ac.jp.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan g44177a@nucc.cc.nagoya-u.ac.jp i45556a@cc.nagoya-u.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hisamoto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001369:Axons / Q000502:physiology*; D019771:Axotomy; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000633:toxicity; D003598:Cytoskeletal Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D020439:Growth Cones / Q000502:physiology; D016023:Integrins / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D018613:Microscopy, Confocal; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000235:genetics / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D003598:Cytoskeletal Proteins; D016023:Integrins; D008164:Luminescent Proteins; D003300:Copper; C517554:Max-2 protein, C elegans; D017346:Protein Serine-Threonine Kinases; D020744:rac GTP-Binding Proteins
keywords: C. elegans; Rac; axon regeneration; signal transduction