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.
Many genetic risk factors for schizophrenia may function in common molecular pathways, contributing to high brain functions. We will explore a role for NDEL1, a genetic risk factor for schizophrenia, in convergence of the nNOS and DISC1 pathways for dendritic development in the neonatal stage, which may be crucial for prfrontal cortex-associated behaviors.
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