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

ABSTRACT: Since the identification of MECP2 as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this disease. The use of additional mammalian RTT models offers the promise of further elucidating critical early mechanisms of disease as well as providing new avenues for translational studies. We have identified significant abnormalities in growth as well as motor and behavioural function in a novel zinc-finger nuclease model of RTT utilizing both male and female rats throughout development. Male rats lacking MeCP2 (Mecp2^ZFN/y) were noticeably symptomatic as early as postnatal day 21, with most dying by postnatal day 55, while females lacking one copy of Mecp2 (Mecp2^ZFN/+) displayed a more protracted disease course. Brain weights of Mecp2^ZFN/y and Mecp2^ZFN/+rats were significantly reduced by postnatal day 14 and 21, respectively. Early motor and breathing abnormalities were apparent in Mecp2^ZFN/y rats, whereas Mecp2^ZFN/+rats displayed functional irregularities later in development. The large size of this species will provide profound advantages in the identification of early disease mechanisms and the development of appropriately timed therapeutics. The current study establishes a foundational basis for the continued utilization of this rat model in future RTT research.

SUBMITTER: Patterson KC

PROVIDER: S-EPMC5179928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome.

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MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome.

Project description:Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio, but decreased food intake compared to wild-type. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together, these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulates early and progressive metabolic and motor phenotypes of human RTT.

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Tsix-Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function.

Project description:Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a mutation in the X-linked methyl-CpG-binding protein 2 (MECP2). There is currently no disease-specific treatment, but MECP2 restoration through reactivation of the inactive X (Xi) has been of considerable interest. Progress toward an Xi-reactivation therapy has been hampered by a lack of suitable female mouse models. Because of cellular mosaicism due to random X-chromosome inactivation (XCI), Mecp2+/- heterozygous females develop only mild RTT. Here, we create an improved female mouse model by introducing a mutation in Tsix, the antisense regulator of XCI allelic choice. Tsix-Mecp2 mice show reduced MECP2 mosaicism and closely phenocopy the severely affected Mecp2-null males. Tsix-Mecp2 females demonstrate shortened lifespan, motor weakness, tremors, and gait disturbance. Intriguingly, they also exhibit repetitive behaviors, as is often seen in human RTT, including excessive grooming and biting that result in self-injury. With a Tsix allelic series, we vary MECP2 levels in brain and demonstrate a direct, but nonlinear correlation between MECP2 levels and phenotypic improvement. As little as 5-10% MECP2 restoration improves neuromotor function and extends lifespan five- to eightfold. Our study thus guides future pharmacological strategies and suggests that partial MECP2 restoration could have disproportionate therapeutic benefit.

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Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin.

Project description:Motor skill deficit is a common and invalidating symptom of Rett syndrome (RTT), a rare disease almost exclusively affecting girls during the first/second year of life. Loss-of-function mutations of the methyl-CpG-binding protein2 (MECP2; Mecp2 in rodents) gene is the cause in most patients. We recently found that fluoxetine, a selective serotonin (5-HT) reuptake inhibitor and antidepressant drug, fully rescued motor coordination deficits in Mecp2 heterozygous (Mecp2 HET) mice acting through brain 5-HT. Here, we asked whether fluoxetine could increase MeCP2 expression in the brain of Mecp2 HET mice, under the same schedule of treatment improving motor coordination. Fluoxetine increased the number of MeCP2 immuno-positive (MeCP2+) cells in the prefrontal cortex, M1 and M2 motor cortices, and in dorsal, ventral and lateral striatum. Fluoxetine had no effect in the CA3 region of the hippocampus or in any of the brain regions of WT mice. Inhibition of 5-HT synthesis abolished the fluoxetine-induced rise of MeCP2+ cells. These findings suggest that boosting 5-HT transmission is sufficient to enhance the expression of MeCP2 in several brain regions of Mecp2 HET mice. Fluoxetine-induced rise of MeCP2 could potentially rescue motor coordination and other deficits of RTT.

| S-EPMC8290043 | biostudies-literature

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