NDEL1 in nNOS/DlSC1 signaling for cortical development and NO-mediated behaviors

精神分裂症-1中断(DISC1)和神经元型一氧化氮合酶(NNOS)，遗传危险因素 精神分裂症(SZ)在神经发育中起着关键作用。项目4的目标是检查 Nude-like 1(NDEL1)，一种SZ相关的DISC1相互作用因子，在nNOS和DISC1通路的汇聚中 前额叶皮质(PFC)的发育和由此产生的行为，并探讨 SZ中的nNOS信号转导。NNOS信号调节神经元分化，如树突发育。AS 结果，nNOS基因敲除(KO)小鼠表现出不同的异常行为。然而，与PFC相关的行为 在nNOS KO小鼠中还没有研究，而与PFC相关的认知缺陷经常 在深圳报道。我们以前报道过DISC1-NDEL1相互作用调节轴突生长。 有趣的是，NDEL1激活了CDC42，这是树突发育的关键调节因子。鉴于nNOS的存在， NDEL1和DISC1在发育中的大脑皮质的皮质板中高表达，NDEL1可能 作为nNOS信号的下游效应因子，在树突状细胞的关键期受DISC1调节 新生儿期的发育。因此，我们假设(1)nNOS和NDEL1由DISC1锚定 对于NDEL1的S-亚硝化，(2)S-NDEL1的亚硝化促进NDEL1从蛋白质中释放 与DISC1的复合体激活CDC42，以及(3)这种信号是树突发育所必需的， 由此产生的行为。这些假设将被测试，重点放在基础神经科学上 行为核心(核心B)。我们将通过宫内电穿孔使用可诱导的基因表达系统， 它只在迁移后神经元中操纵NDEL1的功能。这种创新的方法使 美国将剖析DISC1途径中其他遗传风险因素研究的时间需求，例如 DISC1(项目1)、PCMI和RPGRIPIL(项目2)和DPYSL2/CRMP2(项目3)，以及探索 与SZ相关的动物模型中基因-环境相互作用的分子病理学(项目5和6)。 通过对我们患者队列的遗传分析，将进一步探讨nNOS信号在SZ中的意义 以及与Project 3和Core A合作的nNOS KO小鼠的分子图谱。

Disrupted-in-Schizophrenia-1 (DISC1) and neuronal nitric oxide synthase (nNOS), genetic risk factors for schizophrenia (SZ), have key roles in neurodevelopment. The goal of project 4 is to examine the role for NudE-like 1 (NDEL1), a SZ-associated DISC1 interactor, in convergence of the nNOS and DISC1 pathways for the development of prefrontal cortex (PFC) and resultant behaviors, and to explore the implication of nNOS signaling in SZ. nNOS signaling regulates neuronal differentiation, such as dendritic development. As a result, nNOS knockout (KO) mice display diverse abnormal behaviors. However, PFC-associated behaviors in nNOS KO mice have not yet been studied, whereas PFC-associated cognitive deficits have been frequently reported in SZ. We have previously reported that DISC1-NDEL1 interaction regulates neurite outgrowth. Interestingly, NDEL1 activates Cdc42, a critical regulator for dendritic development. Given that nNOS, NDEL1, and DISC1 are highly expressed in the cortical plate in developing cerebral cortex, NDEL1 may function as a downstream effector of nNOS signaling, regulated by DISC1 for the critical period of dendritic development in the neonatal stage. Thus, we hypothesize that (1) nNOS and NDEL1 are anchored by DISC1 for S-nitrosylation of NDEL1, (2) S-nitrosylation of NDEL1 facilitates the release of NDEL1 from the protein complex with DISC1 for Cdc42 activation, and (3) this signaling is required for dendritic development and resultant behaviors. These hypotheses will be tested with an emphasis on the basic neuroscience with behavioral Core (Core B). We will use an inducible gene expression system via in utero electroporation, which manipulates NDEL1 function exclusively in post-migratory neurons. This innovative approach allows us to dissect the temporal requirement for the studies of other genetic risk factors in DISC1 pathways, such as DISC1 (project 1), PCMI and RPGRIPIL (project 2), and DPYSL2/CRMP2 (project 3), as well as explore the molecular pathology of gene-environment interactions in animal models relevant to SZ (project 5 and 6). The implication of nNOS signaling in SZ will be further explored by genetic analysis of our patient cohort and molecular profile of nNOS KO mice in collaboration with project 3 and Core A.