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c-fos protein expression and ischemic changes in neurons vulnerable to ischemia/hypoxia, correlated with basic
1Department of Pathology, National Cheng Kung University, Medical College, Tainan, Taiwan, R.O.C.
Abstract:
Injuries to the brain induce rapid expression of c-fos and c-jun proto-oncogenes in neurons. The protein products (Fos and Jun) of these cellular immediate early genes are thought to regulate target genes that participate in fundamental biological responses. In recent studies of rat brain infarct we demonstrated that gliosis and angiogenesis, two of the fundamental biological responses, are related to neuronal expression of basic fibroblast growth factor (bFGF). In the present study, we explore the linkage between c-fos and bFGF genes by comparing the temporal and spatial domains of Fos and bFGF immunoreactivities (IR) in brain infarct and in transient global ischemia. We demonstrate colocalization of Fos-IR and ischemic changes in neurons at infarct periphery and in regions of "selective vulnerability" beginning 3 hours post-infarction and lasting up to 1-2 weeks. These are: cortical neurons in layers II-III and V, interneurons in hippocampal formation, cerebellar Purkinje cells, and many subcortical nuclei and brainstem nuclei. bFGF-IR appears 12-24 hours later than Fos-IR in the same region but in non-ischemic neurons and the expression persists beyond 2 weeks. Persistent and not transient c-fos expression appears to be associated with ischemic neuronal death, although some of these neurons may survive beyond 2 weeks postinfarction.
Insights
Brain injuries rapidly activate c-fos and c-jun genes in neurons. Persistent c-fos expression correlates with neuronal death following ischemic events, while bFGF expression follows and persists longer.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- Brain injuries trigger immediate early gene expression, including c-fos and c-jun proto-oncogenes.
- Fos and Jun proteins are transcription factors regulating genes involved in biological responses.
- Previous work linked neuronal basic fibroblast growth factor (bFGF) expression to gliosis and angiogenesis after brain infarct.
Purpose of the Study:
- To investigate the relationship between c-fos and bFGF gene expression in the context of brain ischemia.
- To compare the temporal and spatial patterns of Fos and bFGF immunoreactivity in rat brain infarct and transient global ischemia models.
Main Methods:
- Utilized rat models of brain infarct and transient global ischemia.
- Examined the temporal and spatial distribution of Fos and bFGF immunoreactivities (IR) using immunohistochemistry.
- Identified specific neuronal populations exhibiting these changes, including cortical layers, hippocampal interneurons, Purkinje cells, and various nuclei.
Main Results:
- Fos immunoreactivity colocalized with ischemic changes in neurons at infarct periphery and vulnerable regions starting 3 hours post-infarction, persisting for 1-2 weeks.
- bFGF immunoreactivity appeared 12-24 hours after Fos-IR in the same regions but in non-ischemic neurons.
- bFGF expression persisted beyond 2 weeks, whereas transient c-fos expression was not consistently associated with neuronal death.
Conclusions:
- Persistent c-fos expression is linked to ischemic neuronal death, though some neurons may survive.
- The temporal dissociation between Fos and bFGF expression suggests distinct roles in the ischemic cascade.
- These findings elucidate the molecular responses to brain injury and neuronal cell fate determination.