Dissecting functional roles of schizophrenia risk gene ZNF804a in neural development

? DESCRIPTION (provided by applicant): Mental illnesses like schizophrenia (SZ) and bipolar disease (BP) are devastating brain disorders with global unmet medical needs. Significant accomplishments have identified over a hundred robust and replicable risk loci from genome-wide associated studies (GWAS) during last two years, which may provide novel aspects of the underlying biological basis of SZ and serve as new drug targets for psychiatric disorders. However, molecular functions of many newly-identified risk genes in the nervous system, including ZNF804a, are completely unknown. Thus, there is a critical need to elucidate the underlying molecular processes affected by pathogenic alleles of ZNF804a and other risk genes. Lack of such understanding, treatment options for psychiatric patients carrying similar risk alleles are unlikely to improve substantially. The long-term goal is to elucidate molecular mechanisms that underlie the risks for SZ and to develop novel and effective therapeutic intervention strategies for the treatment of SZ. The objective of this application, therefore, is t further investigate the role of ZNF804a in neuronal development combining both in utero mouse model and in vitro human inducible pluripotent stem cell (iPSC) model. The central hypothesis is that ZNF804a is vital for neuronal differentiation and the disease-associated SNP alters ZNF804a gene expression thereby regulates neuronal differentiation and migration. The rationale for this project is that its successful completion would provide a strong conceptual evidence-based frame-work to study many other noncoding genetic variants associated with SZ and to establish isogenic iPSC clones for future drug development. This central hypothesis will be tested by two Specific Aims: 1) Determine the critical role of ZNF804a in neuronal migration and differentiation in vivo; and 2) Determine the function of ZNF804a and its intronic disease-associated allele using novel isogenic human iPSCs. The research proposal is innovative, in applicant's opinion, because the combination of in vitro iPSC and in vivo mouse models will allow to significantly reduce the genetic heterogeneity in patient-derived iPSC lines and enhance the sensitivity to detect the biological readout for common risk variants. This contribution will be significant because it is the first step to measure the effect of noncoding genetic risk variant on disease-associated phenotypes in a pure genetic background. The human iPSC model may serve as a platform for the future chemical screen to identify small molecules that can correct certain phenotypes associated with SZ and other developmental disorders.