Translational control in neurogenesis by ZNF804A

修改后的项目摘要/摘要部分 精神分裂症(SZ)和躁郁症(BP)等精神疾病是破坏性的大脑疾病，具有全球未得到满足的医疗需求。神经发育理论认为，神经前体细胞(NPC)的产生和分化障碍会导致大脑发育偏离正常路径，导致神经元电路和行为缺陷的改变，这些改变最早出现在青春期或成年期。遗传风险在SZ和BP的病因学中起主要作用，已发现几个强大的、可复制的风险基因座在这两种疾病之间存在显著重叠。在顶级遗传关联中，ZNF804A编码一种锌指蛋白。在自闭症和发育迟缓的患者中也发现了ZNF804A的各种染色体变异，包括缺失和复制。此外，神经成像和神经心理学研究证实，ZNF804A是大脑结构、连接性和行为异常变化的重要遗传预测因子。然而，ZNF804A在神经系统中的分子功能完全未知。因此，迫切需要阐明ZNF804A功能障碍对生命早期大脑发育的影响。我们的中心假设是ZNF804A通过与翻译机制相互作用以及ZNF804A与其他发育基因的遗传相互作用来调节神经元的决定。因此，这项应用的目的是进一步剖析ZNF804A如何调控神经发生的分子细节，并在基因敲除小鼠中检查ZNF804A及其相互作用基因之间的遗传功能相互作用。这一中心假说将通过以下具体目标得到验证：1)确定ZNF804A介导的蛋白质翻译调控机制；2)确定ZNF804A在体内神经元命运承诺中的作用。这项研究方案具有创新性，因为这一策略将体内小鼠实验系统与尖端基因组/蛋白质组技术相结合。这一贡献将是重要的，因为它使我们能够测量ZNF804A对神经发育轨迹的影响，并确定导致发育性大脑疾病的潜在潜在机制。

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.