Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadianclock

Mice carrying a null mutation in the Period 1 (mPer1) gene were generated u sing embryonic stem cell technology. Homozygous mPer1 mutants display a sho rter circadian period with reduced precision and stability. Mice deficient in both mPer1 and mPer2 do not express circadian rhythms. While mPER2 regul ates clock gene expression at the transcriptional level, mPER1 is dispensab le for the rhythmic RNA expression of mPer1 and mPer2 and may instead regul ate mPER2 at a posttranscriptional level. Studies of clock-controlled genes (CCGs) reveal a complex pattern of regulation by mPER1 and mPER2, suggesti ng independent controls by the two proteins over some output pathways. Gene s encoding key enzymes in heme biosynthesis are under circadian control and are regulated by mPER1 and mPER2. Together, our studies show that mPER1 an d mPER2 have distinct and complementary roles in the mouse clock mechanism.