MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

Patterson, Kelsey; Hawkins, Virginia E.; Arps, Kara M.; Mulkey, Daniel K.; Olsen, Michelle L.

doi:10.1093/hmg/ddw179

Cited by 37 publications

(44 citation statements)

References 106 publications

(123 reference statements)

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“…To determine if MeCP2 KO rats show altered nocifensive behaviors, we used standard sensorimotor behavioral tests in MeCP2 KO and WT control rats. The behavioral phenotype of the MeCP2 KO rat has been characterized previously (20)(21)(22) and is similar to that of mouse models (8). Our rats showed lower axon outgrowth from CNS neurons, and reduced ambulatory activity and motor performance at 30-51 d (Fig.…”

Section: Rtt Rats Show Abnormal Mechanical and Temperature Sensitivitysupporting

confidence: 78%

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Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Bhattacherjee

Winter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Children with Rett syndrome show abnormal cutaneous sensitivity. The precise nature of sensory abnormalities and underlying molecular mechanisms remain largely unknown. Rats with methyl-CpG binding protein 2 (MeCP2) mutation, characteristic of Rett syndrome, show hypersensitivity to pressure and cold, but hyposensitivity to heat. They also show cutaneous hyperinnervation by nonpeptidergic sensory axons, which include subpopulations encoding noxious mechanical and cold stimuli, whereas peptidergic thermosensory innervation is reduced. MeCP2 knockdown confined to dorsal root ganglion sensory neurons replicated this phenotype in vivo, and cultured MeCP2-deficient ganglion neurons showed augmented axonogenesis. Transcriptome analysis revealed dysregulation of genes associated with cytoskeletal dynamics, particularly those controlling actin polymerization and focal-adhesion formation necessary for axon growth and mechanosensory transduction. Down-regulation of these genes by topoisomerase inhibition prevented abnormal axon sprouting. We identified eight key affected genes controlling actin signaling and adhesion formation, including members of the Arhgap, Tiam, and cadherin families. Simultaneous virally mediated knockdown of these genes in Rett rats prevented sensory hyperinnervation and reversed mechanical hypersensitivity, indicating a causal role in abnormal outgrowth and sensitivity. Thus, MeCP2 regulates ganglion neuronal genes controlling cytoskeletal dynamics, which in turn determines axon outgrowth and mechanosensory function and may contribute to altered pain sensitivity in Rett syndrome.

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Section: Rtt Rats Show Abnormal Mechanical and Temperature Sensitivitysupporting

confidence: 78%

“…5C). There also appears to be limited overlap between our findings for the DRG and those reported for the hypothalamus of the MeCP2 KO rat (21), suggesting that differences may be tissue-specific.…”

Section: Mecp2 Disruption Selectively Regulates Drg Functional Pathwayscontrasting

confidence: 50%

Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Bhattacherjee

Winter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…2E; Mecp2: 0.86 ± 0.1 s, WT: 0.57 ± 0.04 s, Unpaired t-test, p = 0.013). Additionally, Mecp2 rats performed fewer trials during behavioral training sessions, consistent with previous reports of motor hypoactivity (Bhattacherjee et al, 2017;Guy et al, 2001;Patterson et al, 2016;Samaco et al, 2013;Stearns et al, 2007;Veeraragavan et al, 2015;Wu et al, 2016) (Fig. 2F;Mecp2: 114.29 ± 11.27, WT: 144.19 ± 8.61, Unpaired t-test, p = 0.049).…”

Section: Resultssupporting

confidence: 89%

“…Previous studies report modest de cits in motor function in Mecp2 heterozygous or KO animal models (Bhattacherjee et al, 2017;Guy et al, 2001;Patterson et al, 2016;Samaco et al, 2013;Stearns et al, 2007;Veeraragavan et al, 2015;Wu et al, 2016), but these de cits largely fail to replicate the substantial motor dysfunction observed in Rett patients. Given the appearance of de cits on a challenging auditory task, we next sought to characterize acquisition and performance of Mecp2 rats on a skilled forelimb motor task.…”

Section: Resultsmentioning

confidence: 99%

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

Adcock¹,

Blount

Morrison³

et al. 2020

Preprint

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Background: Rett Syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett Syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett Syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. Methods: We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task. Results: Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT. Conclusions: Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.

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“…RTT animal models were first generated in mice and recently in rats (Chen et al, 2001; Guy et al, 2001; Stearns et al, 2007; Ricceri et al, 2008; Yang et al, 2013; Veeraragavan et al, 2016). It is interesting that RTT-related neurological phenotypes mostly occur in adult male rodents, which is different from the human disease (Lombardi et al, 2015; Patterson et al, 2016; Chen et al, 2001; Glaze, 2004; Guy et al, 2001). It is therefore conceivable that gene-edited nonhuman primates (NHPs) would serve as a better choice for modeling genetic neurological disorders including RTT (Jennings et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

Chen

Niu

et al. 2017

Cell

162

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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MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats

Cited by 37 publications

References 106 publications

Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys

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