The project aims at investigating the contribution of MeCP2 to reprogramming, genomic instability and control of synaptogenesis. Mutations in the MeCP2 gene can cause the Autism Spectrum Disorder (ASD) Rett syndrome (RTT). ASD are complex neurodevelopmental diseases, highly heritable and mainly characterized by deficits in impaired social interaction, and repetitive behavior. The prevalence of ASD has dramatically increased (57%) over the past four years, from 1:150 in 2002 to 1:110 in 2006. Family history and twin studies suggest that, at least in some cases, these disorders share genetic roots, but the degree to which environmental and genetic factors account for individual differences within ASD is currently unknown. A combination of several genetic mutations is likely to play a role in each ASD individual. Mutations and duplication of MeCP2 gene are also observed in other disorders, such as severe neonatal encephalopathy, schizophrenia and X-linked mental retardation. We recently developed an induced pluripotent stem cell (iPSC) system for RTT and showed that MeCP2 is directly involved on the regulation of glutamatergic synapses in human neurons. Also, we demonstrated that MeCP2 is a repressor of L1 retrotransposons, leading to an increase number in somatic mutations. The aims and experiments of this proposal were designed to understand the function of MeCP2 during development. The data generated here will be useful to design novel therapeutic targets for several neurological disorders. The results of this research will have broad implication in the field, with direct consequences for the generation of stem cells free of somatic insertions and the understanding of early stages of synaptic development in human neurons.
Statement of Benefit to California:
Mutations in the MeCP2 gene were linked to several mental disorders, including Rett syndrome (RTT), X-linked mental retardation, severe neonatal encephalopathy, schizophrenia and autism, affecting many Californian children. Because MeCP2 plays an important role in the pathogenesis of multiple disorders, the investigation of MeCP2 function and regulatory pathways in the cell may show promise for developing broad-spectrum therapies. In the absence of a functionally effective cure or early diagnostic tool, the cost of caring for patients with such pediatric diseases is high, in addition to a major personal and family impact since childhood. Our major goal is to understand the regulatory network of MeCP2 molecular interactions in the cells. Our preliminary data strongly suggest that MeCP2 is an important factor for the maintenance of genome stability in stem cells. Moreover, it is also involved in the control of synapses during development. The proposed experiments will bring novel insights on the identification of novel therapeutic targets, potential diagnostics for early detection of several diseases risk, or ability to predict severity of particular symptoms. In addition, the development of this type of validation approach in California will serve as an important proof of principle and stimulate the formation of businesses that seek to develop novel types of therapies in California with consequent economic benefit.