Rhythms in clock proteins in the mouse pars tuberalis depend on MT1 melatonin receptor signalling

Dec 6, 2005The European journal of neuroscience

Daily cycles of clock proteins in a mouse brain area rely on MT1 melatonin receptor signals

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Abstract

In wild type mice, mPER1, mPER2, and mCRY1 exhibit a pronounced rhythm in the hypophyseal pars tuberalis.

Melatonin influences the rhythmic expression of clock genes in the pars tuberalis.
MT1 melatonin receptor-deficient mice show reduced levels of mPER1, mCRY1, CLOCK, and BMAL1.
mPER2 levels are constitutively low in MT1-/- mice despite rhythmic expression of its mRNA.
The presence of mPER1 and mCRY1 appears to stabilize mPER2, suggesting a codependency for its stability.
Melatonin is crucial for regulating the availability of key circadian proteins in pars tuberalis cells.

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Melatonin provides a rhythmic neuroendocrine output, driven by a central circadian clock that encodes information about phase and length of the night. In the hypophyseal pars tuberalis (PT), melatonin is crucial for rhythmic expression of the clock genes mPer1 and mCry1, and melatonin acting in the PT influences prolactin secretion from the pars distalis. To examine further the possibility of a circadian clockwork functioning in the PT, and the impact of melatonin on this tissue, we assessed circadian clock proteins by immunohistochemistry and compared the diurnal expression in the PT of wild type (WT), and MT1 melatonin receptor-deficient (MT1-/-) mice. While in the PT of WT mice mPER1, mPER2, and mCRY1 showed a pronounced rhythm, mCRY2, CLOCK, and BMAL1 were constitutively present. Despite reported differences in maximal levels and timing of mCry1, mPer1, and mPer2 RNAs, the corresponding protein levels peaked simultaneously during late day, suggesting a codependency for their stabilization and/or nuclear entry. MT1-/- mice had reduced levels of mPER1, mCRY1, CLOCK and BMAL1, consistent with the earlier reported reduction in mRNA expression of these clock genes. Surprisingly, mPER2-immunoreaction was constitutively low, although mPer2 was rhythmically expressed in the PT of MT1-/- mice. This suggests that mPER2 is degraded due to the reduced levels of its stabilizing interaction partners mPER1 and mCRY1. The results show that melatonin, acting through the MT1, determines availability of the circadian proteins mPER1, mPER2 and mCRY1 and thus plays a crucial role in regulating rhythmicity in PT cells.

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Rhythms in clock proteins in the mouse pars tuberalis depend on MT1 melatonin receptor signalling

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