title: Proliferating reactive astrocytes are regulated by Notch-1 in the peri-infarct area after stroke.
abstract: OBJECTIVE
  The formation of reactive astrocytes is common after central nervous system injuries such as stroke. However, the signaling pathway(s) that control astrocyte formation and functions are poorly defined. We assess the effects of Notch 1 signaling in peri-infarct-reactive astrocytes after stroke.
  
  
  METHODS
  We examined reactive astrocyte formation in the peri-infarct area 3 days after distal middle cerebral artery occlusion with or without γ-secretase inhibitor treatment. To directly study the effects of inhibiting a γ-secretase cleavage target in reactive astrocytes, we generated glial fibrillary acidic protein-CreER™:Notch 1 conditional knockout mice.
  
  
  RESULTS
  Gamma-secretase inhibitor treatment after stroke decreased the number of proliferative glial fibrillary acidic protein-positive reactive astrocytes and RC2-positive reactive astrocytes directly adjacent to the infarct core. The decrease in reactive astrocytes correlated with an increased number of CD45-positive cells that invaded into the peri-infarct area. To study the influence of reactive astrocytes on immune cell invasion, ex vivo immune cell invasion assays were performed. We found that a γ-secretase-mediated pathway in astrocytes affected Jurkat cell invasion. After tamoxifen treatment, glial fibrillary acidic protein-CreER™:Notch 1 conditional knockout mice had a significantly decreased number of proliferating reactive astrocytes and RC2-positive reactive astrocytes. Tamoxifen treatment also led to an increased number of CD45-positive cells that invaded the peri-infarct area.
  
  
  CONCLUSIONS
  Our results demonstrate that proliferating and RC2-positive reactive astrocytes are regulated by Notch 1 signal transduction and control immune cell invasion after stroke.
authors.affiliation: Department of Anatomy and Neurobiology, University of Vermont, Colchester, VT, USA.
authors.forename: Issei S
authors.initials: IS
authors.lastname: Shimada
authors.forename: Alyssa
authors.initials: A
authors.lastname: Borders
authors.forename: Alexander
authors.initials: A
authors.lastname: Aronshtam
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Spees
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D049109:Cell Proliferation; D002544:Cerebral Infarction / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism* / Q000473:pathology
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1