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The Journal of biological chemistry v.292 no.4, 2017년, pp.1240 - 1250   SCI SCIE
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A Novel Rac1-GSPT1 Signaling Pathway Controls Astrogliosis Following Central Nervous System Injury

Ishii, Taiji (From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, ); Ueyama, Takehiko (From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, ); Shigyo, Michiko (the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan, ); Kohta, Masaaki (the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, ); Kondoh, Takeshi (the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, ); Kuboyama, Tomoharu (the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan, ); Uebi, Tatsuya (From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, ); Hamada, Takeshi (From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, ); Gutmann, David H. (the Department of Neurology, Washington University S ); Aiba, Atsu ( ); Kohmura, Eiji ( ); Tohda, Chihiro ( ); Saito, Naoaki ( );
  • 초록  

    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;Rac1 flox/flox ). GFAP-Cre;Rac1 flox/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 (G 1 to 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.


  • 주제어

    astrocyte .   cell cycle .   cell migration .   cell proliferation .   glial cell .   inflammation .   mouse .   Rac (Rac GTPase) .   CNS injury .   GSPT1.  

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