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

精神分裂症1型（DISC 1）和神经元型一氧化氮合酶（nNOS）， 精神分裂症（SZ）在神经发育中起关键作用。项目4的目标是审查 NudE-like 1（NDEL 1）是一种SZ相关的DISC 1相互作用物，在nNOS和DISC 1通路的会聚中 对前额叶皮层（PFC）发育及其行为的影响，并探讨 SZ中的nNOS信号传导。nNOS信号传导调节神经元分化，例如树突发育。作为 结果，nNOS敲除（KO）小鼠表现出多种异常行为。然而，PFC相关行为 在nNOS KO小鼠中尚未研究，而PFC相关的认知缺陷经常被研究。 在SZ报道。我们以前曾报道过DISC 1-NDEL 1相互作用调节神经突生长。 有趣的是，NDEL 1激活Cdc 42，这是树突发育的关键调节因子。考虑到nNOS， NDEL 1和DISC 1在发育中的大脑皮质的皮质板中高度表达，NDEL 1可能 作为nNOS信号传导的下游效应物，在树突状细胞增殖的关键期由DISC 1调节。 在新生儿阶段的发展。因此，我们假设（1）nNOS和NDEL 1通过DISC 1锚定 对于NDEL 1的S-亚硝基化，（2）NDEL 1的S-亚硝基化促进NDEL 1从蛋白质中释放 与DISC 1复合用于Cdc 42活化，以及（3）这种信号传导是树突发育所需的， 结果行为。这些假设将被测试，重点是基础神经科学， 行为核心（核心B）。我们将通过子宫内电穿孔使用诱导型基因表达系统， 其仅在迁移后神经元中操纵NDEL 1功能。这种创新的方法使 我们剖析了DISC 1途径中其他遗传风险因素研究的时间要求，例如 DISC 1（项目1）、PCMI和RPGRIPIL（项目2）和DPYSL 2/CRMP 2（项目3），以及探索 SZ相关动物模型中基因-环境相互作用的分子病理学（项目5和6）。 通过对我们的患者队列进行遗传分析，将进一步探讨nNOS信号传导在SZ中的意义 和nNOS KO小鼠的分子谱，与项目3和核心A合作。

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.