The project aims at investigating the contribution of MeCP2 to synaptogenesis. MeCP2 is a transcriptional regulator, attracted to methylated DNA. Mutations and duplications of MeCP2 are observed in a large spectrum of neurological disorders, including Rett syndrome (RTT), X-linked mental retardation, severe neonatal encephalopathy, schizophrenia and autism. 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. The aims and experiments of this proposal were designed to understand the function of MeCP2 during development. Using an array of controls and MeCP2 mutant iPSCs lines, we will investigate how MeCP2 levels can contribute to the formation glutamatergic synapses. We will use genetic tools to allow the visualization and quantification of newly synthesized synapses. MeCP2 targets will be tested for causal effects based on a series of gene expression and proteomics experiments. Finally, we will measure the impact of non-neuronal cell types on the synaptic defects observed in RTT neurons. 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 ASDs, with direct consequences for 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 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 human neurons. Our preliminary data strongly suggest that MeCP2 is an important factor for the formation of excitatory synapses during development. The proposed experiments will bring novel insights on the identification of new 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.