Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome.

Surabi Veeraragavan,Shannon M Hamilton,Ying-Wooi Wan,Meagan R Pitcher,Agnes J Liang,Sharon G Huang,Zhandong Liu,Christopher M Mcgraw,Sirena Soriano,Lisa A Yuva,Jeffrey L Neul,Jennie R Green,Janine M Lasalle,Daniel R Connolly,Dag H Yasui,Rodney C Samaco,Richard Paylor,Christopher S Ward

doi:10.1093/hmg/ddw178

Abstract

Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse to identify viable therapies for the human condition may present challenges in translating findings from the bench to the clinic. In addition, the need to identify outcome measures in well-chosen animal models is critical for preclinical trials. Here, we report that a novel Mecp2 rat model displays high face validity for modelling psychomotor regression of a learned skill, a deficit that has not been shown in Mecp2 mice. Juvenile play, a behavioural feature that is uniquely present in rats and not mice, is also impaired in female Mecp2 rats. Finally, we demonstrate that evaluating the molecular consequences of the loss of MeCP2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in the human RTT brain. These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures.

Highlights

Rett syndrome (RTT, MIM 312750) is an X-linked neurodevelopmental disorder caused by mutations in MECP2 [1]
Some loss-of-function Mecp2 mouse models of RTT have good construct validity and mimic either the human disease mutation itself or the consequence of the human disease-causing mutations [3,48,74], the findings from our work indicate the value of the Mecp2 rat model as a powerful tool with the potential to shape the landscape of future studies focused on both mechanisms of RTT pathophysiology as well as on preclinical efforts to ameliorate disease onset and progression
Unlike the conventional homologous recombination approach used to generate the most widely studied Mecp2 germline null mouse model [50], zinc-finger nuclease (ZFN) targeting of the endogenous Mecp2 locus in the rat did not produce a complete null allele; rather, an allele was created in which normal Methyl-CpG-Binding Protein 2 (MeCP2) protein expression was completely abolished yet total abundance of Mecp2 RNA remained unaltered

Summary

Introduction

Rett syndrome (RTT, MIM 312750) is an X-linked neurodevelopmental disorder caused by mutations in MECP2 [1]. Because of the overlapping disease features of RTT with other intellectual disabilities and autism spectrum disorders (IDD/ASD), therapeutic interventions that may help RTT phenotypes may prove useful for the treatment of many neurodevelopmental and neurological conditions. Recent studies in animal models have demonstrated that RTT may be reversible; most notably, many features of the disorder are normalized in mouse models following reexpression of the Mecp gene [26]. The vast majority of experimental therapies for neurological disorders failed to translate successfully from animal models to human disease therapies for reasons such as sub-optimal animal models, poor study design, and the lack of rigorous evaluations [34,35,36,37]

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