title: Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model.
abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linkedMECP2gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (Mecp2A140V "knock-in" mutant) expressing the recurrent humanMECP2A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant (Mecp2A140V/y) and wild type (Mecp2+/y) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele) and a wild typeMecp2gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1) treatment of neuronal cells fromMecp2mutant mice rescued the soma size phenotype. We also found thatMecp2mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an importantin vitrocellular phenotype ofMecp2mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput,in vitroassay to screen for compounds that rescue small neuronal phenotype ("phenotypic assay").
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, USA; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, USA.
authors: Sampathkumar
authors: S
authors: Rangasamy
authors: Barrow Neurological Institute, St.Joseph's Hospital and Medical Center, Phoenix, USA.
authors: Shannon
authors: S
authors: Olfers
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, USA; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, USA; School of Life Sciences, Arizona State University, Tempe, USA.
authors: Brittany
authors: B
authors: Gerald
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, USA; School of Life Sciences, Arizona State University, Tempe, USA.
authors: Alex
authors: A
authors: Hilbert
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, USA; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, USA.
authors: Sean
authors: S
authors: Svejda
authors: Neurogenomics Division, Translational Genomics Research Institute, Phoenix, USA; Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, USA; Barrow Neurological Institute, St.Joseph's Hospital and Medical Center, Phoenix, USA; School of Life Sciences, Arizona State University, Tempe, USA.
authors: Vinodh
authors: V
authors: Narayanan
keywords: Cerebellar granule neurons; Hippocampal neuronal cultures; IGF-1; MECP2; Neuronal nuclear size; Neuronal soma size; Rett syndrome; Rictor; mTOR pathway