title: Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome.
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.
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Surabi
authors.initials: S
authors.lastname: Veeraragavan
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Ying-Wooi
authors.initials: YW
authors.lastname: Wan
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Connolly
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Hamilton
authors.affiliation: Department of Pediatrics, Section of Neurology.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Ward
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Sirena
authors.initials: S
authors.lastname: Soriano
authors.affiliation: Program in Translational Biology and Molecular Medicine.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Meagan R
authors.initials: MR
authors.lastname: Pitcher
authors.affiliation: Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: McGraw
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Sharon G
authors.initials: SG
authors.lastname: Huang
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Jennie R
authors.initials: JR
authors.lastname: Green
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Yuva
authors.affiliation: Department of Molecular and Human Genetics.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Agnes J
authors.initials: AJ
authors.lastname: Liang
authors.affiliation: Department of Pediatrics, Section of Neurology.|Program in Translational Biology and Molecular Medicine.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Neul
authors.affiliation: Rowe Program in Human Genetics, University of California Davis, Davis, CA, USA.
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.affiliation: Rowe Program in Human Genetics, University of California Davis, Davis, CA, USA.
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
authors.affiliation: Department of Pediatrics, Section of Neurology.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Zhandong
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Richard
authors.initials: R
authors.lastname: Paylor
authors.affiliation: Department of Molecular and Human Genetics rodney.samaco@bcm.edu.|Program in Translational Biology and Molecular Medicine.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
authors.forename: Rodney C
authors.initials: RC
authors.lastname: Samaco
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2