Schizophrenia risk gene ZNF804A controls ribosome localization and synaptogenesis in developing human neurons

ZNF804A was amongst the first genes robustly associated with schizophrenia based on findings from large-scale genomic studies. Previous research has implicated ZNF804A inthe regulation of gene expression and synaptic function, but the role this gene plays inneurodevelopment and in relation to schizophrenia pathogenesis remains unclear. To study the function of this gene during neurodevelopment, we generated isogenichuman induced pluripotent stem cells (hiPSCs) with reduced ZNF804A expression, differentiated them into developing cortical glutamatergic neurons and studied theirtranscriptomic, synaptic and protein signatures. Mutant neurons showed modest changes in gene expression. However, high-content confocal imaging revealed increased excitatory synapse density in mutant neurons. Cell-compartment specific proteomic analysis further revealed that mutant neurons had higher levels of ribosomal andtranslational proteins in their neurites, and high-content imaging confirming increased local protein synthesis efficiency. Overall, these results demonstrate that in human developing cortical glutamatergic neurons, ZNF804A regulates excitatory synapse formation potential via increased local protein translation. Overall design: This study aimed to investigate the role of the schizophrenia susceptibility gene ZNF804A through transcriptomic analysis in a relevant cellular model. We conducted a comprehensive expression profile of ZNF804A during glutamatergic cell development, identifying immature post-mitotic forebrain neurons as a suitable model. CRISPR/Cas9 genome editing was employed to induce mutations in ZNF804A, and bulk RNAseq was performed to assess transcriptional changes.