This proposal is based on several key findings, described in detail in Background and Significance and in Preliminary Results: 1) The genes for Neuregulin 1 (NRG1) and the NRG1 receptor ERBB4 appear to represent susceptibility loci for schizophrenia, and their gene products demonstrate abnormalities in postmortem studies;2) We have identified an ERBB4 signaling complex comprised of ERBB4, a MAGI scaffolding protein, and a receptor phosphotyrosine phosphatase (RPTP);3) We have evidence that PTPRZ1, the gene coding for RPTPb (as well as for the secreted phosphacan splice variants), represents a schizophrenia susceptibility locus (gene-wide P=0.007;best P=0.0002): RPTPb plays an important role in oligodendrocyte development and in neuron-glia signaling;and, 5) Analysis of mRNA expression data indicates that RPTPb and RPTPb-binding proteins show expression abnormalities in schizophrenia. These findings lead to our overarching hypothesis: alterations in PTPRZ1/RPTPb signaling cause dysfunction of oligodendrocyte development and/or function with resultant myelin deficits, and can thereby contribute to schizophrenia susceptibility. In this project, we will characterize the role of PRPTZ1 and RPTPb in schizophrenia, using genetic and postmortem expression studies, as well as cell biological and animal models. Through these analyses, our aim is to establish a causal involvement of PTPRZ1/RPTPb signaling abnormalities in aspects of the schizophrenia phenotype.
Our specific aims are: 1. To further determine whether PTPRZI/RPTPb, and associated signaling components, are altered in schizophrenia;2. To characterize the function of PTPRZI/RPTPb, and associated signaling components, in oligodendrocyte development and myelin formation in cell culture systems;and, 3. To analyze the effects of perturbation of the molecular components of PTPRZ1 signaling on oligodendrocyte development and function, white matter coherence, and behavior in animals. We will work closely with Administrative Core, Clinical Core/Brain bank, and Statistics Core, and Project 1, 2, 4, and 5, to accomplish these aims. Through these analyses, we hope to establish the causal involvement of PTPRZ1 -signaling abnormalities in oligodendrocytes in aspects of the schizophrenia phenotype.
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