Role of heterozygous and homozygous alleles in cryptochrome-deficient mice

The circadian rhythms of physiology and behavior are based on molecular systems at the cellular level, which are regulated by clock genes, including cryptochrome genes, Cry1 and Cry2. In mammals, the circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus maintains the circadian rhythms throughout the body. Cry1 and Cry2 play distinct roles in regulating the circadian rhythm. However, the different effects of manipulating clock genes in heterozygous and homozygous alleles, Cry1 and Cry2, remain unclear. Therefore, this study aimed to understand the haplosufficiency of cryptochrome genes in regulating the circadian system. We examined wheel-running activity rhythms and PER2::LUC expression rhythms in SCN slices and pituitary explants in mice. Compared with wild-type mice, Cry1^-/- or Cry2^-/- mice had shortened or lengthened periods in free-running behavioral rhythms and PER2::LUC expression in the SCN and pituitary gland. Cry1^+/- mice had similar circadian rhythms as wild-type mice, although Cry2^+/- mice had lengthened periods. The amplitude of PER2::LUC expression exhibited faster damping in Cry1^-/- mice. Therefore, Cry1 deficiency affects the circadian period length and stability of the circadian system. A single allele of Cry2 deficiency affects the circadian rhythm, whereas that of Cry1 deficit is compensated.