Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9-based Rett syndrome model mouse


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Abstract

Methyl-CpG-binding protein 2 (Mecp2) is an X-linked gene encoding a methylated DNA-binding nuclear protein which regulates transcriptional activity. The mutation ofMECP2in 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 inMecp2-deficient mice. We successfully generated both male and femaleMecp2-deficient mice on the wild-type C57BL/6 background andPER2Luciferase(PER2Luc) knock-in background using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system. GeneratedMecp2-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 ofPER2Luc-driven circadian oscillation was significantly attenuated inMecp2-deficient SCN neurons. On the other hand,in vitrocircadian rhythm development assay usingMecp2-deficient mouse embryonic stem cells (ESCs) did not show amplitude changes ofPER2Lucbioluminescence rhythms. Together, these results show thatMecp2deficiency abrogates the circadian pacemaking ability of the SCN, which may be a therapeutic target to treat the sleep problems of patients with RTT.

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