Capire i meccanismi cellulari alla base della sindrome di Rett

Backgroud Rett syndrome (RS) is a progressive neurodevelopmental disorder with onset in early childhood characterized by motor abnormalities, mental retardation, anxiety and autism. Most cases of RS have been linked to loss of function of MECP2 (Methyl CpG-binding Protein) gene. Since MECP2 is localized on the X chromosome, affected females have one normal and one defective copy of the gene. The affected females are characterized by genetic mosaicism since each cell inactivates randomly one of the two copies of the X chromosome. Therefore the body is formed by two cell population expressing either normal MeCP2 or the mutated form. One of the most effective models for the study of MeCP2 function,  is a mouse model in which MeCP2 can be removed by the activity of a specific enzyme. In these mice it should be possible to reproduce the mosaic of expression present in affected females to understand whether the functional defects are directly caused by the MeCP2 mutation or if they are a consequence of a deeply altered brain ecosystem. Our proposal was centered on the creation of a novel model for MeCP2 in which we could replicate the mosaic characteristic of the human disease while tagging each neuron with a fluorescent protein, with red indicating a normal genotype, while green indicates the loss of MeCP2. Results We have designed a genetic tools that creates a mosaic of expression of MeCP2 which is revealed by the selective expression of two different fluorescent proteins. A red protein tags the neurons carrying the wild type MeCP2 while mutated neurons express a green fluorescence. By using this tool we can analyze and compare the function of normal and diseased neurons placed in the mixed genotype that constitutes the characteristic genetic landscape of Rett syndrome. At this time we are studying neuronal development and migration, the development of excitatory synapses and soon we will be able to compare the physiology of normal and diseased neurons and how they interact together. Perspectives These studies will provide a framework to identify what are the direct biochemical and physiological consequences of the loss of MECP2. This will allow a better understanding of the basis of Rett syndrome and possibly will provide clues for activating plastic changes in the non-mutated neurons that might partially vicariate for the defective neuronal pathways. Finally, the approach that we have developed will be useful for the study of other pathologies characterized by genetic mosaicism.