Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

Sarah D. Schlatterer, Hyeon sook Suh, Concepcion Conejero-Goldberg, Shufen Chen, Christopher M. Acker, Sunhee C. Lee, Peter Davies

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number208
JournalJournal of Neuroinflammation
Volume9
DOIs
StatePublished - Aug 31 2012

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Interferons
Cell Cycle
Gliosis
Prosencephalon
Bromodeoxyuridine
Pathology
Gene Expression
Neurons
Hippocampus
abl Genes
Pathologic Processes
Immunoblotting
Protein Kinases
Reverse Transcription
Up-Regulation
Immunohistochemistry
Inflammation
Polymerase Chain Reaction
Brain

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

Schlatterer, S. D., Suh, H. S., Conejero-Goldberg, C., Chen, S., Acker, C. M., Lee, S. C., & Davies, P. (2012). Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways. Journal of Neuroinflammation, 9, [208]. https://doi.org/10.1186/1742-2094-9-208

Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways. / Schlatterer, Sarah D.; Suh, Hyeon sook; Conejero-Goldberg, Concepcion; Chen, Shufen; Acker, Christopher M.; Lee, Sunhee C.; Davies, Peter.

In: Journal of Neuroinflammation, Vol. 9, 208, 31.08.2012.

Research output: Contribution to journalArticle

Schlatterer, SD, Suh, HS, Conejero-Goldberg, C, Chen, S, Acker, CM, Lee, SC & Davies, P 2012, 'Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways', Journal of Neuroinflammation, vol. 9, 208. https://doi.org/10.1186/1742-2094-9-208
Schlatterer, Sarah D. ; Suh, Hyeon sook ; Conejero-Goldberg, Concepcion ; Chen, Shufen ; Acker, Christopher M. ; Lee, Sunhee C. ; Davies, Peter. / Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways. In: Journal of Neuroinflammation. 2012 ; Vol. 9.
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