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Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons.

ABSTRACT: Where a neuron is positioned in the brain during development determines neuronal circuitry and information processing needed for normal brain function. When aberrations in this process occur, cognitive disorders may result. Patients diagnosed with schizophrenia have been reported to show altered neuronal connectivity and heterotopias. To elucidate pathways by which this process occurs and become aberrant, we have chosen to study the long isoform of nitric oxide synthase 1 adaptor protein (NOS1AP), a protein encoded by a susceptibility gene for schizophrenia.To determine whether NOS1AP plays a role in cortical patterning, we knocked down or co-overexpressed NOS1AP and a green fluorescent protein or red fluorescent protein (TagRFP) reporter in neuronal progenitor cells of the embryonic rat neocortex using in utero electroporation. We analyzed sections of cortex (ventricular zone, intermediate zone, and cortical plate [CP]) containing green fluorescent protein or red fluorescent protein TagRFP positive cells and counted the percentage of positive cells that migrated to each region from at least three rats for each condition.NOS1AP overexpression disrupts neuronal migration, resulting in increased cells in intermediate zone and less cells in CP, and decreases dendritogenesis. Knockdown results in increased migration, with more cells reaching the CP. The phosphotyrosine binding region, but not the PDZ-binding motif, is necessary for NOS1AP function. Amino acids 181 to 307, which are sufficient for NOS1AP-mediated decreases in dendrite number, have no effect on migration.Our studies show for the first time a critical role for the schizophrenia-associated gene NOS1AP in cortical patterning, which may contribute to underlying pathophysiology seen in schizophrenia.

SUBMITTER: Carrel D

PROVIDER: S-EPMC4416077 | biostudies-other | 2015 Jun

REPOSITORIES: biostudies-other

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Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons.

Carrel Damien D Hernandez Kristina K Kwon Munjin M Mau Christine C Trivedi Meera P MP Brzustowicz Linda M LM Firestein Bonnie L BL

Biological psychiatry 20141030 11

<h4>Background</h4>Where a neuron is positioned in the brain during development determines neuronal circuitry and information processing needed for normal brain function. When aberrations in this process occur, cognitive disorders may result. Patients diagnosed with schizophrenia have been reported to show altered neuronal connectivity and heterotopias. To elucidate pathways by which this process occurs and become aberrant, we have chosen to study the long isoform of nitric oxide synthase 1 adap ...[more]

PMID: 25542305

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Project description:TSNARE1, which encodes the protein tSNARE1, is a high-confidence gene candidate for schizophrenia risk, but nothing is known about its cellular or physiological function. We identified the major gene products of TSNARE1 and their cytoplasmic localization and function in endosomal trafficking in cortical neurons. We validated three primary isoforms of TSNARE1 expressed in human brain, all of which encode a syntaxin-like Qa SNARE domain. RNA-sequencing data from adult and fetal human brain suggested that the majority of tSNARE1 lacks a transmembrane domain that is thought to be necessary for membrane fusion. Biochemical data demonstrate that tSNARE1 can compete with Stx12 for incorporation into an endosomal SNARE complex, supporting its possible role as an inhibitory SNARE. Live-cell imaging in cortical neurons from mice of both sexes demonstrated that brain tSNARE1 isoforms localized to the endosomal network. The most abundant brain isoform, tSNARE1c, localized most frequently to Rab7+ late endosomes, and endogenous tSNARE1 displayed a similar localization in human neural progenitor cells and neuroblastoma cells. In mature rat neurons from both sexes, tSNARE1 localized to the dendritic shaft and dendritic spines, supporting a role for tSNARE1 at the postsynapse. Expression of either tSNARE1b or tSNARE1c, which differ only in their inclusion or exclusion of an Myb-like domain, delayed the trafficking of the dendritic endosomal cargo Nsg1 into late endosomal and lysosomal compartments. These data suggest that tSNARE1 regulates endosomal trafficking in cortical neurons, likely by negatively regulating early endosomal to late endosomal trafficking.SIGNIFICANCE STATEMENT Schizophrenia is a severe and polygenic neuropsychiatric disorder. Understanding the functions of high-confidence candidate genes is critical toward understanding how their dysfunction contributes to schizophrenia pathogenesis. TSNARE1 is one of the high-confidence candidate genes for schizophrenia risk, yet nothing was known about its cellular or physiological function. Here we describe the major isoforms of TSNARE1 and their cytoplasmic localization and function in the endosomal network in cortical neurons. Our results are consistent with the hypothesis that the majority of brain tSNARE1 acts as a negative regulator to endolysosomal trafficking.

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Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons.

Publications

Nitric oxide synthase 1 adaptor protein, a protein implicated in schizophrenia, controls radial migration of cortical neurons.

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