Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT

Li, Quan; Loh, Dawn H.; Kudo, Takashi; Truong, Danny; Derakhshesh, Matthew; Kaswan, Zoë MacDowell; Ghiani, Cristina A.; Tsoa, Rosemarie W.; Chen, Yin; Sun, Yi; Colwell, Christopher S.

doi:10.1016/j.nbd.2015.03.009

Cited by 37 publications

(59 citation statements)

References 56 publications

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“…Remarkably, sleep in mutants was more fragmented than that in control monkeys, with more bouts of awaking and sleep (Figure 4A, b–d). It seemed difficult for mutant monkeys to have a continuous and longer-hour sleep, which is similar to RTT patients with abnormal circadian rhythms as well as Mecp2 mutant mice (Li et al., 2015). …”

Section: Resultsmentioning

confidence: 99%

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Chen

Niu

et al. 2017

Cell

171

131

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Summary Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.

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Section: Resultsmentioning

confidence: 99%

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Chen

Niu

et al. 2017

Cell

171

131

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“…also have reported that circadian behavioral activity rhythms and PER2 Luc bioluminescence rhythms are compromised in a hemizygous Mecp2 −/y mouse model of RTT (Li et al . ). As the results shown in our study were compatible with those reported data, our CRISPR/Cas9‐based approach confirmed that Mecp2 deficiency resulted in the attenuation of the circadian molecular oscillation in the SCN as well as the disruption of the circadian behavioral rhythm.…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2015

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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.

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“…Indeed, double-targeting of both miRs was demonstrated for mRNAs [40] implicated e.g. in circadian functions [41]. …”

Section: Discussionmentioning

confidence: 99%

Genetic background-dependent effects of murine micro RNAs on circadian clock function

et al. 2017

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MicroRNAs (miRs) are important regulators of a wide range of biological processes. Antagomir studies suggest an implication of miR-132 in the functionality of the mammalian circadian clock. miR-212 and miR-132 are tandemly processed from the same transcript and share the same seed region. We found the clock modulator miR-132 and miR-212 to be expressed rhythmically in the central circadian clock. Consequently, mRNAs implicated in circadian functions may likely be targeted by both miRs. To further characterize the circadian role we generated mice with stable deletion of the miR-132/212 locus and compared the circadian behavior of mutant and wild-type control animals on two genetic backgrounds frequently used in chronobiological research, C57BL/6N and 129/Sv. Surprisingly, the wheel-running activity phenotype of miR mutant mice was highly background specific. A prolonged circadian free-running period in constant darkness was found in 129/Sv, but not in C57BL/6N miR-132/212 knockout mice. In contrast, in C57BL/6N, but not in 129/Sv miRNA-132/212 knockout mice a lengthened free-running period was observed in constant light conditions. Furthermore, miR-132/212 knockout mice on 129/Sv background exhibited enhanced photic phase shifts of locomotor activity accompanied by reduced light induction of Period gene transcription in the SCN. This phenotype was absent in miRNA-132/212 knockout mice on a C57BL/6N background. Together, our results reveal a strain and light regimen-specific function of miR-132/212 in the circadian clock machinery suggesting that miR-132 and miR-212 act as background-dependent circadian rhythm modulators.

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Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT

Cited by 37 publications

References 56 publications

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

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

Genetic background-dependent effects of murine micro RNAs on circadian clock function

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