title: A Novel Rac1-GSPT1 Signaling Pathway Controls Astrogliosis Following Central Nervous System Injury.
abstract: Astrogliosis (i.e. glial scar), which is comprised primarily of proliferated astrocytes at the lesion site and migrated astrocytes from neighboring regions, is one of the key reactions in determining outcomes after CNS injury. In an effort to identify potential molecules/pathways that regulate astrogliosis, we sought to determine whether Rac/Rac-mediated signaling in astrocytes represents a novel candidate for therapeutic intervention following CNS injury. For these studies, we generated mice with Rac1 deletion under the control of the GFAP (glial fibrillary acidic protein) promoter (GFAP-Cre;Rac1flox/flox). GFAP-Cre;Rac1flox/flox(Rac1-KO) mice exhibited better recovery after spinal cord injury and exhibited reduced astrogliosis at the lesion site relative to control. Reduced astrogliosis was also observed in Rac1-KO mice following microbeam irradiation-induced injury. Moreover, knockdown (KD) or KO of Rac1 in astrocytes (LN229 cells, primary astrocytes, or primary astrocytes from Rac1-KO mice) led to delayed cell cycle progression and reduced cell migration. Rac1-KD or Rac1-KO astrocytes additionally had decreased levels of GSPT1 (G1to S phase transition 1) expression and reduced responses of IL-1β and GSPT1 to LPS treatment, indicating that IL-1β and GSPT1 are downstream molecules of Rac1 associated with inflammatory condition. Furthermore, GSPT1-KD astrocytes had cell cycle delay, with no effect on cell migration. The cell cycle delay induced by Rac1-KD was rescued by overexpression of GSPT1. Based on these results, we propose that Rac1-GSPT1 represents a novel signaling axis in astrocytes that accelerates proliferation in response to inflammation, which is one important factor in the development of astrogliosis/glial scar following CNS injury.
authors.affiliation: From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Ishii
authors.affiliation: From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, tueyama@kobe-u.ac.jp.
authors.forename: Takehiko
authors.identifier: 0000-0002-5647-3937
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Shigyo
authors.affiliation: the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kohta
authors.affiliation: the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondoh
authors.affiliation: the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Kuboyama
authors.affiliation: From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Uebi
authors.affiliation: From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hamada
authors.affiliation: the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, and.
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.affiliation: the Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.affiliation: the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kohmura
authors.affiliation: the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tohda
authors.affiliation: From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, naosaito@kobe-u.ac.jp.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D005911:Gliosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010454:Peptide Termination Factors / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D009479:Neuropeptides; D010454:Peptide Termination Factors; C484602:Rac1 protein, mouse; C087971:peptide-chain-release factor 3; D020830:rac1 GTP-Binding Protein
keywords: CNS injury; GSPT1; Rac (Rac GTPase); astrocyte; cell cycle; cell migration; cell proliferation; glial cell; inflammation; mouse