Disruption of Me CP 2 attenuates circadian rhythm in CRISPR /Cas9‐based Rett syndrome model mouse

Methyl‐CpG‐binding protein 2 ( Mecp2 ) is an X‐linked gene encoding a methylated DNA ‐binding nuclear protein which regulates transcriptional activity. The mutation of MECP 2 in humans is associated with Rett syndrome ( RTT ), a neurodevelopmental disorder. Patients with RTT frequently show abnormal sleep patterns and sleep‐associated problems, in addition to autistic symptoms, raising the possibility of circadian clock dysfunction in RTT . In this study, we investigated circadian clock function in Mecp2 ‐deficient mice. We successfully generated both male and female Mecp2 ‐deficient mice on the wild‐type C57 BL /6 background and PER 2 Luciferase ( PER 2 Luc ) knock‐in background using the clustered regularly interspaced short palindromic repeats ( CRISPR )/Cas9 system. Generated Mecp2 ‐deficient mice recapitulated reduced activity in mouse models of RTT , and their activity rhythms were diminished in constant dark conditions. Furthermore, real‐time bioluminescence imaging showed that the amplitude of PER 2 Luc ‐driven circadian oscillation was significantly attenuated in Mecp2 ‐deficient SCN neurons. On the other hand, in vitro circadian rhythm development assay using Mecp2 ‐deficient mouse embryonic stem cells ( ESC s) did not show amplitude changes of PER 2 Luc bioluminescence rhythms. Together, these results show that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN , which may be a therapeutic target to treat the sleep problems of patients with RTT .