title: Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways.
abstract: BACKGROUND
  Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice.
  
  
  METHODS
  To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry.
  
  
  RESULTS
  Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected.
  
  
  CONCLUSIONS
  Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in neurons, and that the AblPP/tTA mouse may be an excellent model for studying sterile inflammation and the effects of interferon signaling in the brain.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Schlatterer
authors.forename: Hyeon-sook
authors.initials: HS
authors.lastname: Suh
authors.forename: Concepcion
authors.initials: C
authors.lastname: Conejero-Goldberg
authors.forename: Shufen
authors.initials: S
authors.lastname: Chen
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Acker
authors.forename: Sunhee C
authors.initials: SC
authors.lastname: Lee
authors.forename: Peter
authors.initials: P
authors.lastname: Davies
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D007372:Interferons / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009833:Olfactory Pathways / Q000378:metabolism; D016374:Oncogene Proteins v-abl / Q000235:genetics; D016548:Prosencephalon / Q000166:cytology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D016374:Oncogene Proteins v-abl; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007372:Interferons; D001973:Bromodeoxyuridine; D004318:Doxycycline