RRC ID 48852
Author Renault-Mihara F, Mukaino M, Shinozaki M, Kumamaru H, Kawase S, Baudoux M, Ishibashi T, Kawabata S, Nishiyama Y, Sugai K, Yasutake K, Okada S, Nakamura M, Okano H.
Title Regulation of RhoA by STAT3 coordinates glial scar formation.
Journal J. Cell Biol.
Abstract Understanding how the transcription factor signal transducer and activator of transcription-3 (STAT3) controls glial scar formation may have important clinical implications. We show that astrocytic STAT3 is associated with greater amounts of secreted MMP2, a crucial protease in scar formation. Moreover, we report that STAT3 inhibits the small GTPase RhoA and thereby controls actomyosin tonus, adhesion turnover, and migration of reactive astrocytes, as well as corralling of leukocytes in vitro. The inhibition of RhoA by STAT3 involves ezrin, the phosphorylation of which is reduced in STAT3-CKO astrocytes. Reduction of phosphatase and tensin homologue (PTEN) levels in STAT3-CKO rescues reactive astrocytes dynamics in vitro. By specific targeting of lesion-proximal, reactive astrocytes in Nestin-Cre mice, we show that reduction of PTEN rescues glial scar formation in Nestin-Stat3+/- mice. These findings reveal novel intracellular signaling mechanisms underlying the contribution of reactive astrocyte dynamics to glial scar formation.
Volume 216(8)
Pages 2533-2550
Published 2017-8-7
DOI 10.1083/jcb.201610102
PII jcb.201610102
PMID 28642362
PMC PMC5551705
MeSH Actomyosin / metabolism Animals Animals, Newborn Astrocytes / enzymology* Astrocytes / pathology Cell Adhesion Cell Movement Cells, Cultured Cicatrix / enzymology* Cicatrix / genetics Cicatrix / pathology Coculture Techniques Cytoskeletal Proteins / genetics Cytoskeletal Proteins / metabolism Disease Models, Animal Genotype Integrases / genetics Macrophages / metabolism Matrix Metalloproteinase 2 / genetics Matrix Metalloproteinase 2 / metabolism Mice, Inbred C57BL Mice, Knockout MicroRNAs / genetics MicroRNAs / metabolism Nestin / genetics Neuroglia / enzymology* Neuroglia / pathology PTEN Phosphohydrolase / genetics PTEN Phosphohydrolase / metabolism Phenotype Phosphorylation Proteolysis STAT3 Transcription Factor / deficiency STAT3 Transcription Factor / genetics STAT3 Transcription Factor / metabolism* Signal Transduction Spinal Cord / enzymology* Spinal Cord / pathology Spinal Cord Injuries / enzymology* Spinal Cord Injuries / genetics Spinal Cord Injuries / pathology Transfection Wounds, Stab / enzymology* Wounds, Stab / genetics Wounds, Stab / pathology rho GTP-Binding Proteins / genetics rho GTP-Binding Proteins / metabolism* rho-Associated Kinases / metabolism
IF 8.891
Resource
Mice B6.129P2-Pten<tm2Mak>(RBRC02300)