Mitogen‐ and stress‐activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock

Nov 7, 2012The European journal of neuroscience

A protein called MSK1 influences how the brain’s circadian clock adjusts to light

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Abstract

MSK1 null mice exhibited a significantly longer free-running period than wild-type controls.

MSK1 null mice successfully entrained to a 12 h light/dark cycle and maintained circadian rhythms in constant darkness.
The free-running period was longer and showed greater variance in activity onset in MSK1 null mice compared to wild-type mice.
These mice had a significant reduction in the phase-delaying response to an early night light pulse.
MSK1 knockout animals displayed a significantly delayed rate of re-entrainment in an 8 h phase-advancing 'jet-lag' experiment.
Key molecular responses, such as early night light-induced phosphorylation of CREB and histones, as well as Period1 gene expression, were markedly reduced in MSK1 null mice.

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The master circadian clock in mammals, the suprachiasmatic nucleus (SCN), is under the entraining influence of the external light cycle. At a mechanistic level, intracellular signaling via the p42/44 mitogen-activated protein kinase pathway appears to play a central role in light-evoked clock entrainment; however, the precise downstream mechanisms by which this pathway influences clock timing are not known. Within this context, we have previously reported that light stimulates activation of the mitogen-activated protein kinase effector mitogen-stress-activated kinase 1 (MSK1) in the SCN. In this study, we utilised MSK1(-/-) mice to further investigate the potential role of MSK1 in circadian clock timing and entrainment. Locomotor activity analysis revealed that MSK1 null mice entrained to a 12 h light/dark cycle and exhibited circadian free-running rhythms in constant darkness. Interestingly, the free-running period in MSK1 null mice was significantly longer than in wild-type control animals, and MSK1 null mice exhibited a significantly greater variance in activity onset. Further, MSK1 null mice exhibited a significant reduction in the phase-delaying response to an early night light pulse (100 lux, 15 min), and, using an 8 h phase-advancing 'jet-lag' experimental paradigm, MSK1 knockout animals exhibited a significantly delayed rate of re-entrainment. At the molecular level, early night light-evoked cAMP response element-binding protein (CREB) phosphorylation, histone phosphorylation and Period1 gene expression were markedly attenuated in MSK1(-/-) animals relative to wild-type mice. Together, these data provide key new insights into the molecular mechanisms by which MSK1 affects the SCN clock.

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Mitogen‐ and stress‐activated protein kinase 1 modulates photic entrainment of the suprachiasmatic circadian clock

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