This proposal is based on several key findings, described in detail in Background and Significance and inPreliminary Results: 1) The genes for Neuregulin 1 (NRG1) and the NRG1 receptor ERBB4 appear torepresent susceptibility loci for schizophrenia, and their gene products demonstrate abnormalities inpostmortem studies; 2) We have identified an ERBB4 signaling complex comprised of ERBB4, a MAGIscaffolding protein, and a receptor phosphotyrosine phosphatase (RPTP); 3) We have evidence thatPTPRZ1, the gene coding for RPTPb (as well as for the secreted phosphacan splice variants), represents aschizophrenia susceptibility locus (gene-wide P=0.007; best P=0.0002): RPTPb plays an important role inoligodendrocyte development and in neuron-glia signaling; and, 5) Analysis of mRNA expression dataindicates that RPTPb and RPTPb-binding proteins show expression abnormalities in schizophrenia. Thesefindings lead to our overarching hypothesis: alterations in PTPRZ1/RPTPb signaling cause dysfunction ofoligodendrocyte development and/or function with resultant myelin deficits, and can thereby contribute toschizophrenia susceptibility.In this project, we will characterize the role of PRPTZ1 and RPTPb in schizophrenia, using genetic andpostmortem expression studies, as well as cell biological and animal models. Through these analyses, ouraim is to establish a causal involvement of PTPRZ1/RPTPb signaling abnormalities in aspects of theschizophrenia phenotype.
Our specific aims are: 1. To further determine whether PTPRZI/RPTPb, andassociated signaling components, are altered in schizophrenia; 2. To characterize the function ofPTPRZI/RPTPb, and associated signaling components, in oligodendrocyte development and myelinformation in cell culture systems; and, 3. To analyze the effects of perturbation of the molecular componentsof PTPRZ1 signaling on oligodendrocyte development and function, white matter coherence, and behavior inanimals. We will work closely with Administrative Core, Clinical Core/Brain bank, and Statistics Core, andProject 1, 2, 4, and 5, to accomplish these aims. Through these analyses, we hope to establish the causalinvolvement of PTPRZ1 -signaling abnormalities in oligodendrocytes in aspects of the schizophreniaphenotype.
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