Translational control in neurogenesis by ZNF804A

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Modified Project Summary/Abstract Section Mental illnesses like schizophrenia (SZ) and bipolar disease (BP) are devastating brain disorders with global unmet medical needs. The “neurodevelopmental” theory posits that disturbances in the production and differentiation of neural progenitor cells (NPCs) cause brain development to deviate from its normal path, leading to alterations in neuronal circuitry and behavioral deficits that first manifest themselves in adolescence or adulthood. Genetic risk plays a major role in the etiology of SZ and BP and several robust and replicable risk loci have been identified with significant overlap between these two disorders. Among the top genetic associations, ZNF804A encodes a zinc finger protein. Diverse chromosomal variants of ZNF804A, including deletions and duplications, have also been found in patients with autism and developmental delay. Moreover, neuroimaging and neuropsychological studies have confirmed ZNF804A as an important genetic predictor of abnormal changes in brain structures, connectivity and behavior. However, molecular functions of ZNF804A in the nervous system are completely unknown. Thus, there is a critical need to elucidate the impacts of ZNF804A dysfunction on brain development in early life. Our central hypothesis is that ZNF804A regulates neuronal determination through interacting with translational machinery, and genetic interactions of ZNF804A with other developmental genes. The objective of this application, therefore, is to further dissect the molecular details on how ZNF804A modulates neurogenesis, and to examine genetic functional interactions between ZNF804A and its interacting genes in the knockout mice. This central hypothesis will be tested by following Specific Aims: 1) Define the mechanism of ZNF804A-mediated regulation of protein translation; 2) Determine the role of ZNF804A in neuronal fate commitment in vivo. The research proposal is innovative because this strategy combines in vivo mouse experimental systems with cutting-edge genomic/proteomic techniques. This contribution will be significant because it allows us to measure the effect of ZNF804A on the trajectory of neurodevelopment, and to identify potential underlying mechanisms contributing to developmental brain disorders.