Reference:
Miralv?s Julie
Abstract:
Rett syndrome is a severe progressive neurodevelopmental disorder caused by dominant mutations in the MECP2 gene. The MeCP2 protein, highly expressed in mature neurons, is a transcriptional repressor of the family of Methyl-CpG-binding proteins (MBP) characterized by their ability to bind to methylated CpG nucleotides. Although the molecular mechanisms responsible for Rett syndrome remain unclear, it seems likely that this condition is due to uncontrolled expression of normally repressed by MeCP2 gene in neurons. A key step in the understanding of this disease will be to identify the target genes of MeCP2. My thesis consisted in evaluating the hypothesis that the genes encoding MHC class I, rich in CpG islands could be controlled by MeCP2 in the central nervous system (CNS). Indeed, these molecules are involved in the preparation of fine neuronal connections during synaptogenesis in brain plasticity and then are actively repressed in mature neurons. The molecules of class I MHC expression thus have a profile within the complex CNS active and must be finely regulated. So we considered that in the absence of MeCP2, a deregulation of MHC genes may not only alter the immunological status of nervous tissue but also disrupt the establishment and remodeling of neuronal connections, and thus contribute to the progression of the pathology develops in patients with Rett syndrome. A model of transient transfection of murine neuronal lineage allowed us to demonstrate that overexpression of MeCP2 leads to a specific reduced basal and inducible expression of MHC molecules of class I cell surface. However, this repression does not appear to be involved in the pathogenesis of Rett syndrome. Indeed, we generated forms of MeCP2 carrying mutations corresponding to those responsible for the syndrome and found they had a suppression of activity comparable to wild forms MHC. However, MeCP2 seems to be endowed with immunomodulatory functions in the periphery. Characterization of immune-deficient mice MeCP2 has indeed helped raise significant alterations in their mood populations and splenic architecture. Finally, my thesis work has also led us to discover the ability of MeCP2 to be transmitted very efficiently between adjacent cells within neuronal populations and species in a tissue-specific fashion. The exploration of the molecular mechanisms and physiological relevance of this phenomenon is currently underway. Finally, this work could lead to new insights of the pathophysiological mechanisms involved in Rett syndrome.
PROJECT DETAILS
beginning: 2006.
end: 2007.
Country of research: France
Counry of funding source: France
Funding organization: French Medical Research Foundation
Financing: PRIVATE FUNDERS – 16 920 €