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Role of Bcl-2 in the brain-derived neurotrophic factor survival response
T E Allsopp1, S Kiselev, S Wyatt
1School of Biological and Medical Sciences, St Andrews University, Fife, UK.
Abstract:
Developing neurons die if they fail to obtain an adequate supply of neurotrophins from their targets but how neurotrophins suppress cell death is not known. Although over-expression of exogenous Bcl-2 can prevent the death of cultured neurons deprived of members of the nerve growth factor family of neurotrophins it is not known if this effect is physiologically relevant. To determine if Bcl-2 participates in the neurotrophin survival response we used antisense bcl-2 RNA to inhibit endogenous Bcl-2 expression. Here we show that brain-derived neurotrophic factor (BDNF)-dependent neurons are killed by antisense bcl-2 RNA in the presence of BDNF. However, when these neurons were supported with ciliary neurotrophic factor (CNTF) their survival was not affected by antisense bcl-2 RNA. Likewise, the survival of CNTF-dependent ciliary neurons was not affected by antisense bcl-2 RNA. Our findings suggest that Bcl-2 is required for the BDNF survival response and that alternative, Bcl-2-independent survival mechanisms operate in sensory and parasympathetic neurons exposed to CNTF.
Insights
Neurotrophins like brain-derived neurotrophic factor (BDNF) prevent neuron death, but the mechanism is unclear. This study shows Bcl-2 is crucial for BDNF-mediated neuron survival, with alternative pathways for ciliary neurotrophic factor (CNTF).
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Neurotrophins are essential for neuronal survival during development.
- The precise molecular mechanisms by which neurotrophins prevent apoptosis remain largely unknown.
- The anti-apoptotic protein Bcl-2 has been implicated in neurotrophin-mediated survival, but its physiological relevance is debated.
Purpose of the Study:
- To investigate the role of endogenous Bcl-2 in neurotrophin-dependent neuronal survival.
- To determine if Bcl-2 is required for survival mediated by brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF).
Main Methods:
- Utilized antisense bcl-2 RNA to inhibit endogenous Bcl-2 expression in developing neurons.
- Examined the survival of BDNF-dependent and CNTF-dependent neurons under conditions of Bcl-2 inhibition.
- Compared the effects of antisense bcl-2 RNA on neurons supported by BDNF versus CNTF.
Main Results:
- Antisense bcl-2 RNA treatment resulted in the death of BDNF-dependent neurons, even in the presence of BDNF.
- However, CNTF-dependent neurons survived treatment with antisense bcl-2 RNA when supported by CNTF.
- This indicates a differential requirement for Bcl-2 in mediating survival signals from different neurotrophins.
Conclusions:
- Bcl-2 is a necessary component of the survival pathway activated by BDNF.
- Alternative, Bcl-2-independent survival mechanisms are utilized by sensory and parasympathetic neurons when supported by CNTF.
- These findings elucidate distinct molecular pathways underlying neurotrophin-mediated neuronal survival.