PMID- 27941025 OWN - NLM STAT- MEDLINE DCOM- 20170605 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 292 IP - 4 DP - 2017 Jan 27 TI - A Novel Rac1-GSPT1 Signaling Pathway Controls Astrogliosis Following Central Nervous System Injury. PG - 1240-1250 LID - 10.1074/jbc.M116.748871 [doi] AB - 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-1beta and GSPT1 to LPS treatment, indicating that IL-1beta 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. CI - (c) 2017 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Ishii, Taiji AU - Ishii T AD - From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan. FAU - Ueyama, Takehiko AU - Ueyama T AUID- ORCID: 0000-0002-5647-3937 AD - From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, tueyama@kobe-u.ac.jp. FAU - Shigyo, Michiko AU - Shigyo M AD - the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan. FAU - Kohta, Masaaki AU - Kohta M AD - the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. FAU - Kondoh, Takeshi AU - Kondoh T AD - the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. FAU - Kuboyama, Tomoharu AU - Kuboyama T AD - the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan. FAU - Uebi, Tatsuya AU - Uebi T AD - From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan. FAU - Hamada, Takeshi AU - Hamada T AD - From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan. FAU - Gutmann, David H AU - Gutmann DH AD - the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, and. FAU - Aiba, Atsu AU - Aiba A AD - the Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-0033, Japan. FAU - Kohmura, Eiji AU - Kohmura E AD - the Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. FAU - Tohda, Chihiro AU - Tohda C AD - the Division of Neuromedical Science, Department of Bioscience, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan. FAU - Saito, Naoaki AU - Saito N AD - From the Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan, naosaito@kobe-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161209 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (IL1B protein, mouse) RN - 0 (Interleukin-1beta) RN - 0 (Neuropeptides) RN - 0 (Peptide Termination Factors) RN - 0 (Rac1 protein, mouse) RN - 0 (peptide-chain-release factor 3) RN - EC 3.6.5.2 (rac1 GTP-Binding Protein) SB - IM MH - Animals MH - Astrocytes/*metabolism/pathology MH - Gliosis/genetics/*metabolism/pathology MH - Interleukin-1beta/genetics/metabolism MH - Mice MH - Mice, Knockout MH - Neuropeptides/genetics/*metabolism MH - Peptide Termination Factors/genetics/*metabolism MH - Spinal Cord Injuries/genetics/*metabolism/pathology MH - rac1 GTP-Binding Protein/genetics/*metabolism PMC - PMC5270470 OTO - NOTNLM OT - CNS injury OT - GSPT1 OT - Rac (Rac GTPase) OT - astrocyte OT - cell cycle OT - cell migration OT - cell proliferation OT - glial cell OT - inflammation OT - mouse EDAT- 2016/12/13 06:00 MHDA- 2017/06/06 06:00 PMCR- 2018/01/27 CRDT- 2016/12/13 06:00 PHST- 2016/07/21 00:00 [received] PHST- 2016/11/29 00:00 [revised] PHST- 2016/12/13 06:00 [pubmed] PHST- 2017/06/06 06:00 [medline] PHST- 2016/12/13 06:00 [entrez] PHST- 2018/01/27 00:00 [pmc-release] AID - S0021-9258(20)32111-6 [pii] AID - M116.748871 [pii] AID - 10.1074/jbc.M116.748871 [doi] PST - ppublish SO - J Biol Chem. 2017 Jan 27;292(4):1240-1250. doi: 10.1074/jbc.M116.748871. Epub 2016 Dec 9.