Disruption of MeCP2 attenuates circadian rhythm in CRISPR/Cas9‐based Rett syndrome model mouse. (12th October 2015)

• Record Type: Journal Article
• Authors: Tsuchiya, Yoshiki; Minami, Yoichi; Umemura, Yasuhiro; Watanabe, Hitomi; Ono, Daisuke; Nakamura, Wataru; Takahashi, Tomoyuki; Honma, Sato; Kondoh, Gen; Matsuishi, Toyojiro; Yagita, Kazuhiro
• Is Part Of: Genes to cells. Volume 20:Number 12(2015:Dec.)
• Page Start: 992
• Page End: 1005
• Publication Date: 2015-10-12
• Subjects: Cytogenetics -- Periodicals; Cells -- Mechanical properties -- Periodicals; Molecular genetics -- Periodicals; Genes -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Biomechanics -- Periodicals; 571.6
• DOI: 10.1111/gtc.12305
• Languages: English
• ISSNs: 1356-9597

Abstract

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 of MECP2 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 C57BL/6 background and PER2 Luciferase ( PER2 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 PER2 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 (ESCs) did not show amplitude changes of PER2 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. Abstract : Rett syndrome (RTT), a neurodevelopmental disorder that is caused by a mutation of MECP2, is frequently associated with abnormal sleep patterns and sleep‐associated problems. Here, we generated Mecp2‐deficient mice using the CRISPR/Cas9 system and show that the circadian oscillation of PER2Luc reporter expression in the suprachiasmatic nucleus (SCN) was significantly attenuated in Mecp2‐deficient mice as well as their activity rhythms. These data indicate that Mecp2 deficiency abrogates the circadian pacemaking ability of the SCN.