title: The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway.
abstract: The Rac-Cofilin pathway is essential for cytoskeletal remodeling to control axonal development. Rac signals through the canonical Rac-Pak-LIMK pathway to suppress Cofilin-dependent axonal growth and through a Pak-independent non-canonical pathway to promote outgrowth. Whether this non-canonical pathway converges to promote Cofilin-dependent F-actin reorganization in axonal growth remains elusive. We demonstrate that Sickie, a homolog of the human microtubule-associated protein neuron navigator 2, cell-autonomously regulates axonal growth of Drosophila mushroom body (MB) neurons via the non-canonical pathway. Sickie was prominently expressed in the newborn F-actin-rich axons of MB neurons. A sickie mutant exhibited axonal growth defects, and its phenotypes were rescued by exogenous expression of Sickie. We observed phenotypic similarities and genetic interactions among sickie and Rac-Cofilin signaling components. Using the MARCM technique, distinct F-actin and phospho-Cofilin patterns were detected in developing axons mutant for sickie and Rac-Cofilin signaling regulators. The upregulation of Cofilin function alleviated the axonal defect of the sickie mutant. Epistasis analyses revealed that Sickie suppresses the LIMK overexpression phenotype and is required for Pak-independent Rac1 and Slingshot phosphatase to counteract LIMK. We propose that Sickie regulates F-actin-mediated axonal growth via the non-canonical Rac-Cofilin pathway in a Slingshot-dependent manner.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan Graduate Program in Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Abe
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamazaki
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hiroi
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Nitta
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Maeyama
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan Graduate Program in Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan ttabata@iam.u-tokyo.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tabata
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D004330:Drosophila / Q000254:growth & development* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D054461:Lim Kinases / Q000378:metabolism; D024521:Mushroom Bodies / Q000166:cytology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; C000594933:sick protein, Drosophila; D054461:Lim Kinases; C448559:ssh protein, Drosophila; D010749:Phosphoprotein Phosphatases; D020830:rac1 GTP-Binding Protein
keywords: Axon development; Drosophila mushroom body; F-actin; Microtubule; Neuron navigator/UNC-53; Rac-Cofilin pathway; Slingshot LIMK