Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies.

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2025-01-07 DOI:10.1038/s44319-024-00362-9

Saori Toyoda, Masataka Kikuchi, Yoshifumi Abe, Kyosei Tashiro, Takehisa Handa, Shingo Katayama, Yukiko Motokawa, Kenji F Tanaka, Hidehiko Takahashi, Hiroki Shiwaku

{"title":"Schizophrenia-related Xpo7 haploinsufficiency leads to behavioral and nuclear transport pathologies.","authors":"Saori Toyoda, Masataka Kikuchi, Yoshifumi Abe, Kyosei Tashiro, Takehisa Handa, Shingo Katayama, Yukiko Motokawa, Kenji F Tanaka, Hidehiko Takahashi, Hiroki Shiwaku","doi":"10.1038/s44319-024-00362-9","DOIUrl":null,"url":null,"abstract":"Recent genetic studies by the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium have identified that protein-truncating variants of exportin 7 (XPO7) can increase the risk of schizophrenia (odds ratio, 28.1). Here we show that mice with Xpo7 haploinsufficiency (Xpo7+/- mice) present with cognitive and social behavioral impairments. Through proteome analysis using immunoprecipitation and frontal cortex nuclear isolation of Xpo7+/- mice, we identify 45 molecules interacting with Xpo7, including CutC, Rbfox3, and Gria3. Through single-nucleus RNA sequencing of the frontal cortex and striatum of Xpo7+/- mice differentiating between the onset and progressive stages, we also identify 284 gene expression changes that correlate with these stages. These genes encompass high-odds risk genes of schizophrenia identified by SCHEMA, including Gria3, Grin2A, Herc1, and Trio. Furthermore, our approach reveals 15 gene expression changes in the frontal cortex that correlate with the progressive stages. Our findings indicate the importance of investigating whether the interactions among the high-risk genes identified by SCHEMA contribute to a common schizophrenia pathology and underscore the significance of stage-dependent analysis.","PeriodicalId":11541,"journal":{"name":"EMBO Reports","volume":" ","pages":""},"PeriodicalIF":6.5000,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"EMBO Reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1038/s44319-024-00362-9","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Recent genetic studies by the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA) consortium have identified that protein-truncating variants of exportin 7 (XPO7) can increase the risk of schizophrenia (odds ratio, 28.1). Here we show that mice with Xpo7 haploinsufficiency (Xpo7^+/- mice) present with cognitive and social behavioral impairments. Through proteome analysis using immunoprecipitation and frontal cortex nuclear isolation of Xpo7^+/- mice, we identify 45 molecules interacting with Xpo7, including CutC, Rbfox3, and Gria3. Through single-nucleus RNA sequencing of the frontal cortex and striatum of Xpo7^+/- mice differentiating between the onset and progressive stages, we also identify 284 gene expression changes that correlate with these stages. These genes encompass high-odds risk genes of schizophrenia identified by SCHEMA, including Gria3, Grin2A, Herc1, and Trio. Furthermore, our approach reveals 15 gene expression changes in the frontal cortex that correlate with the progressive stages. Our findings indicate the importance of investigating whether the interactions among the high-risk genes identified by SCHEMA contribute to a common schizophrenia pathology and underscore the significance of stage-dependent analysis.

查看原文本刊更多论文

精神分裂症相关的Xpo7单倍不足导致行为和核转运病理。

最近由精神分裂症外显子组测序荟萃分析（SCHEMA）联盟进行的遗传学研究发现，输出蛋白7 （XPO7）的蛋白截断变体可以增加精神分裂症的风险（优势比，28.1）。本研究表明，Xpo7单倍缺陷小鼠（Xpo7+/-小鼠）存在认知和社会行为障碍。通过免疫沉淀和额叶皮质核分离对Xpo7+/-小鼠进行蛋白质组学分析，我们鉴定出45个与Xpo7相互作用的分子，包括CutC、Rbfox3和Gria3。通过对区分发病期和进展期的Xpo7+/-小鼠额叶皮层和纹状体的单核RNA测序，我们还发现了284个与这些阶段相关的基因表达变化。这些基因包括图式识别的精神分裂症高危基因，包括Gria3、Grin2A、Herc1和Trio。此外，我们的方法揭示了前额皮质中与进展阶段相关的15个基因表达变化。我们的研究结果表明，调查由图式确定的高危基因之间的相互作用是否有助于共同的精神分裂症病理的重要性，并强调阶段依赖分析的重要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

期刊介绍： EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry.