Translational control in neurogenesis by ZNF804A

修改项目摘要/摘要部分 精神分裂症（SZ）和双相情感障碍（BP）等精神疾病是全球未满足医疗需求的毁灭性脑部疾病。“神经发育”理论认为，神经祖细胞（NPC）的产生和分化的干扰会导致大脑发育偏离其正常路径，导致神经元回路和行为缺陷的改变，这些改变首先在青春期或成年期表现出来。遗传风险在SZ和BP的病因学中起着重要作用，并且已经确定了几个稳健且可复制的风险位点，这两种疾病之间存在显著重叠。ZNF 804 A编码一种锌指蛋白。ZNF 804 A的各种染色体变异，包括缺失和重复，也在自闭症和发育迟缓患者中发现。此外，神经影像学和神经心理学研究证实，ZNF 804 A是大脑结构、连接和行为异常变化的重要遗传预测因子。然而，ZNF 804 A在神经系统中的分子功能完全未知。因此，迫切需要阐明ZNF 804 A功能障碍对生命早期大脑发育的影响。我们的中心假设是，ZNF 804 A通过与翻译机制相互作用以及ZNF 804 A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，本申请的目的是进一步剖析ZNF 804 A如何调节神经发生的分子细节，并检查敲除小鼠中ZNF 804 A及其相互作用基因之间的遗传功能相互作用。本研究的主要目的是：1）明确ZNF 804 A介导的蛋白质翻译调控机制; 2）确定ZNF 804 A在体内神经元命运定型中的作用。该研究方案具有创新性，因为该策略将体内小鼠实验系统与尖端的基因组/蛋白质组学技术相结合。这一贡献将是重要的，因为它使我们能够测量ZNF 804 A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.