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The olfactory system as a model for the analysis of the contribution of gene expression to programmed cell death
1Roche Institute of Molecular Biology, Roche Research Center, Nutley, NJ 07110, USA.
Abstract:
The process of programmed cell death is frequently attenuated by inhibitors of protein and RNA synthesis. This implies that gene expression is necessary for the active elimination of some cell types. Genes such as bcl-2 and bax have been implicated in the direct control of cell death, while cellular immediate-early genes (cIEGs), such as c-fos and c-jun have been repeatedly associated with neuronal degeneration. We are using the olfactory neuroepithelium as a model system to investigate the role that expression of such genes might play in cell death. The advantages of this system is that even in the adult, there is spontaneous degeneration of olfactory receptor neurons followed by their replacement by the division and differentiation of precursors. Furthermore, the receptor neurons can be induced to die synchronously by removal of the olfactory bulb or intranasal administration of toxic agents. We have generated fos-lacZ and jun-lacZ transgenic mice that can be used to assess expression of c-fos and c-jun following these various manipulations. In addition, a line of transgenic mice has been derived that express Bcl-2 under the control of the olfactory receptor protein promoter. These mice have high levels of Bcl-2 selectively in receptor neurons of the primary neuro-epithelium and vomeronasal organ. Since in some circumstances, Bcl-2 can protect against programmed cell death these mice are being assessed for neuronal turnover under basal conditions and following olfactory bulbectomy.
Insights
Gene expression, including immediate-early genes (cIEGs) and bcl-2, is crucial for programmed cell death in the olfactory system. Researchers used transgenic mice to study gene roles in neuronal degeneration and regeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Programmed cell death (PCD) is often regulated by gene expression.
- Cellular immediate-early genes (cIEGs), like c-fos and c-jun, are linked to neuronal degeneration.
- bcl-2 and bax genes are directly involved in controlling cell death.
Purpose of the Study:
- Investigate the role of gene expression in cell death using the olfactory neuroepithelium model.
- Utilize transgenic mice to track c-fos and c-jun expression and Bcl-2's protective effects.
Main Methods:
- Employing the olfactory neuroepithelium due to spontaneous neuronal turnover and inducible degeneration.
- Generating fos-lacZ and jun-lacZ transgenic mice to monitor c-fos and c-jun expression.
- Developing transgenic mice with neuron-specific Bcl-2 expression to assess its neuroprotective role.
Main Results:
- The study established a model system in the olfactory neuroepithelium for studying gene-mediated cell death.
- Transgenic mice models were created to analyze the expression of key genes involved in neuronal survival and death.
- Bcl-2's potential role in protecting olfactory receptor neurons was investigated under various conditions.
Conclusions:
- Gene expression plays a significant role in the active elimination and regeneration of olfactory receptor neurons.
- The developed transgenic mouse models provide valuable tools for dissecting the molecular mechanisms of neuronal cell death and survival.
- Further research is warranted to fully elucidate the complex interplay of genes in olfactory neurogenesis and degeneration.
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