Project 2

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Schizophrenia (SZ) is a common disorder of largely obscure etiopathology. Epidemiological studies have highlighted the strong influence of genetic susceptibility on the development of the disease, which, in turn, raised the expectation that the identification of susceptibility loci will illuminate the causative cellular pathways. Despite substantial effort, success in this area has been relatively modest. Although numerous studies have mapped potential SZ loci, the number of replicated associations remains scarce. Moreover, even for bona fide SZ genes, the causative alleles remain elusive. Although there are many reasons for this, the most poignant confounding hurdle is the combination of genetic and allelic heterogeneity. Recent data by us and our collaborators, as well as the breadth of expertise in this Program offers the unique opportunity to approach SZ genetics from a combinatorial genetics and functional strategy. Together with colleagues from the proposed Center, we have shown that members of the pericentriolar matrix (centrosome, basal body) contribute alleles to the pathogenesis of psychiatric illness by virtue of loss of function defects that perturb the structure of the centrosome and affect bioth developmental and adult neurogenesis. As part of the Program, we will extend these findings in three ways. We will focus first on PCM1, a protein which, together with Project 1, we have shown to bind to DISC1 and to harbor loss of function mutations in SZ patients. To extend these observations, we will collaborate with Core C and screen a large SZ cohort and identify all coding variants likely detrimental to gene and protein function; these will be tested functionally in a combination of in vivo and in vitro systems drawing from expense both from our group, as well as from Projects 1 and 3 as well as Core B. Second, our data suggest that PCM1 null alleles render susceptibility to SZ; we will model this by ablating (both globally and conditionally) PCM1 in mice and assaying for any anatomical and behavior phenotypes. Finally, we will extend out studies to a series of novel pericentriolar proteins identified in the lab and assay a) whether suppression of these phenocopies the in vitro and in vivo phenotypes of PCM1 and DISC1; and b) whether alleles and/or haplotypes in these loci are associated with SZ (with Core C). These studies, together with the other Center groups, will enhance our understaning of the etiopathology of SZ and will provide both new genetic markers and potential therapeutic pathways.