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Dynamic regulation of c-Jun N-terminal kinase activity in mouse brain by environmental stimuli
1Gladstone Molecular Neurobiology Program and Department of Neurology, University of California, San Francisco, CA 94141, USA. xiao_xu@quickmail.ucsf.edu
Abstract:
Activation of the recently identified c-Jun N-terminal kinases (JNKs) typically results in programmed cell death (apoptosis) in neurons and other cell types grown in culture. However, the effects of JNK activation in the central nervous system in vivo are unknown. At baseline, JNK activity in mice was on average 17-fold higher in brain than in peripheral organs, whereas JNK protein levels were similar. In brain, JNK was expressed primarily in neurons. Restraining mice or allowing them to explore a novel environment rapidly increased JNK activity 3- to 15-fold in various brain regions, but these manipulations did not increase brain activity of the extracellular signal-regulated kinase. Because noninvasive environmental stimuli that do not induce neurodegeneration elicited prominent increases in JNK activity in the brain, we conclude that acute activation of the JNK cascade in central nervous system neurons does not induce neuronal apoptosis in vivo. In contrast, the high baseline activity of JNK in the brain and the activation of the JNK cascade by environmental stimuli suggest that this kinase may play an important physiological role in neuronal function.
Insights
Activation of c-Jun N-terminal kinases (JNKs) in the brain does not cause neuronal death in vivo. Environmental stimuli increase JNK activity, suggesting a physiological role in neuronal function.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- c-Jun N-terminal kinases (JNKs) activation typically induces apoptosis in cultured cells.
- The in vivo effects of JNK activation in the central nervous system (CNS) remain largely unknown.
- JNK is primarily expressed in neurons within the brain.
Purpose of the Study:
- To investigate the in vivo effects of JNK activation in the CNS.
- To determine if JNK activation in the brain leads to neuronal apoptosis.
- To explore the physiological role of JNK in the brain.
Main Methods:
- Measuring JNK activity in mouse brain and peripheral organs at baseline.
- Assessing JNK activity in response to environmental stimuli (restraint, novel environment).
- Evaluating extracellular signal-regulated kinase (ERK) activity under similar conditions.
Main Results:
- Baseline JNK activity was significantly higher in the brain (17-fold) than in peripheral organs.
- Environmental stimuli rapidly increased JNK activity in various brain regions (3- to 15-fold).
- These stimuli did not increase ERK activity in the brain, and no signs of neurodegeneration were observed.
Conclusions:
- Acute JNK activation in CNS neurons in vivo does not induce apoptosis.
- High baseline JNK activity and its activation by environmental stimuli suggest a physiological role in neuronal function.
- JNK signaling may be crucial for normal brain function under physiological conditions.