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Loss of circadian rhythmicity in aging mPer1-/-mCry2-/- mutant mice
Henrik Oster1, Stephanie Baeriswyl, Gijsbertus T J Van Der Horst
1Department of Medicine, Division of Biochemistry, University of Fribourg, 1700 Fribourg, Switzerland.
Abstract:
The mPer1, mPer2, mCry1, and mCry2 genes play a central role in the molecular mechanism driving the central pacemaker of the mammalian circadian clock, located in the suprachiasmatic nuclei (SCN) of the hypothalamus. In vitro studies suggest a close interaction of all mPER and mCRY proteins. We investigated mPER and mCRY interactions in vivo by generating different combinations of mPer/mCry double-mutant mice. We previously showed that mCry2 acts as a nonallelic suppressor of mPer2 in the core clock mechanism. Here, we focus on the circadian phenotypes of mPer1/mCry double-mutant animals and find a decay of the clock with age in mPer1-/- mCry2-/- mice at the behavioral and the molecular levels. Our findings indicate that complexes consisting of different combinations of mPER and mCRY proteins are not redundant in vivo and have different potentials in transcriptional regulation in the system of autoregulatory feedback loops driving the circadian clock.
Insights
The core circadian clock genes mPer1 and mCry2 interact in vivo. Loss of both genes causes age-related clock decay at behavioral and molecular levels, showing non-redundant roles in circadian regulation.
Area of Science:
- Chronobiology
- Molecular Biology
- Genetics
Background:
- The mammalian circadian clock, centered in the suprachiasmatic nuclei (SCN), relies on core clock genes like mPer1, mPer2, mCry1, and mCry2.
- In vitro studies suggest extensive interactions among mPER and mCRY proteins.
Purpose of the Study:
- To investigate in vivo interactions between mPER and mCRY proteins.
- To characterize the circadian phenotypes of mPer1/mCry double-mutant mice, focusing on mPer1-/- mCry2-/-.
- To determine if mPER/mCRY protein complexes are redundant in vivo.
Main Methods:
- Generation of various mPer/mCry double-mutant mouse lines.
- Behavioral analysis of circadian phenotypes in mutant mice.
- Molecular analysis of clock gene expression in mutant mice.
Main Results:
- Age-dependent decay of circadian rhythms was observed in mPer1-/- mCry2-/- mice at both behavioral and molecular levels.
- Findings indicate that mPER and mCRY protein complexes are not functionally redundant in vivo.
- Different mPER/mCRY combinations exhibit distinct transcriptional regulatory potentials.
Conclusions:
- mPER and mCRY proteins form non-redundant complexes essential for robust circadian clock function.
- The specific composition of mPER/mCRY complexes influences their role in the autoregulatory feedback loops of the circadian clock.
- These interactions are critical for maintaining circadian rhythmicity throughout the lifespan.