Differential neuronal functions of LNX1 and LNX2 revealed by behavioural analysis in single and double knockout mice.

IF 4.7 2区 心理学 Q1 BEHAVIORAL SCIENCES
Laura Cioccarelli, Joan A Lenihan, Leah G Erwin, Paul W Young
{"title":"Differential neuronal functions of LNX1 and LNX2 revealed by behavioural analysis in single and double knockout mice.","authors":"Laura Cioccarelli, Joan A Lenihan, Leah G Erwin, Paul W Young","doi":"10.1186/s12993-025-00276-z","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Ligand of NUMB protein-X 1 (LNX1) and LNX2 proteins are closely related PDZ domain-containing E3 ubiquitin ligases that interact with and potentially modulate numerous synaptic and neurodevelopmentally important proteins. While both LNX1 and LNX2 are expressed in neurons, it is noteworthy that neuronal LNX1 isoforms lack the catalytic domain responsible for ubiquitination of substrates. Thus, the shared interaction partners of LNX1 and LNX2 might be differentially regulated by these proteins, with LNX1 acting as a stabilizing scaffold while LNX2 may promote their ubiquitination and degradation. Despite the identification of many LNX interacting proteins and substrates, our understanding of the distinct in vivo functions of LNX1 and LNX2 remains very incomplete.</p><p><strong>Results: </strong>We previously reported that mice lacking both LNX1 in the central nervous system and LNX2 globally exhibit decreased anxiety-related behaviour. Here we significantly extend this work by examining anxiety-related and risk-taking behaviours in Lnx1<sup>-/-</sup> and Lnx2<sup>-/-</sup> single knockout animals for the first time and by analysing previously unexplored aspects of behaviour in both single and double knockout animals. While the absence of both LNX1 and LNX2 contributes to the decreased anxiety-related behaviour of double knockout animals in the open field and elevated plus maze tests, the elimination of LNX2 plays a more prominent role in altered behaviour in the dark-light emergence test and wire beam bridge risk-taking paradigms. By contrast, Lnx knockout mice of all genotypes were indistinguishable from wildtype animals in the marble burying, stress-induced hyperthermia and novel object recognition tests. Analysis of the ultrasonic vocalizations of pups following maternal separation revealed significant differences in call properties and vocal repertoire for Lnx1<sup>-/-</sup> and Lnx1<sup>-/-</sup>;Lnx2<sup>-/-</sup> double knockout animals. Finally, decreased body weight previously noted in double knockout animals could be attributed largely to Lnx1 gene knockout.</p><p><strong>Conclusions: </strong>These results identify specific roles of LNX1 and LNX2 proteins in modulating distinct aspects of anxiety and risk-taking behaviour and social communication in mice. They also reveal an unexpected role for neuronally expressed LNX1 isoforms in determining body weight. These novel insights into the differential neuronal functions of LNX1 and LNX2 proteins provide a foundation for mechanistic studies of these phenomena.</p>","PeriodicalId":8729,"journal":{"name":"Behavioral and Brain Functions","volume":"21 1","pages":"13"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020136/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Behavioral and Brain Functions","FirstCategoryId":"102","ListUrlMain":"https://doi.org/10.1186/s12993-025-00276-z","RegionNum":2,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Ligand of NUMB protein-X 1 (LNX1) and LNX2 proteins are closely related PDZ domain-containing E3 ubiquitin ligases that interact with and potentially modulate numerous synaptic and neurodevelopmentally important proteins. While both LNX1 and LNX2 are expressed in neurons, it is noteworthy that neuronal LNX1 isoforms lack the catalytic domain responsible for ubiquitination of substrates. Thus, the shared interaction partners of LNX1 and LNX2 might be differentially regulated by these proteins, with LNX1 acting as a stabilizing scaffold while LNX2 may promote their ubiquitination and degradation. Despite the identification of many LNX interacting proteins and substrates, our understanding of the distinct in vivo functions of LNX1 and LNX2 remains very incomplete.

Results: We previously reported that mice lacking both LNX1 in the central nervous system and LNX2 globally exhibit decreased anxiety-related behaviour. Here we significantly extend this work by examining anxiety-related and risk-taking behaviours in Lnx1-/- and Lnx2-/- single knockout animals for the first time and by analysing previously unexplored aspects of behaviour in both single and double knockout animals. While the absence of both LNX1 and LNX2 contributes to the decreased anxiety-related behaviour of double knockout animals in the open field and elevated plus maze tests, the elimination of LNX2 plays a more prominent role in altered behaviour in the dark-light emergence test and wire beam bridge risk-taking paradigms. By contrast, Lnx knockout mice of all genotypes were indistinguishable from wildtype animals in the marble burying, stress-induced hyperthermia and novel object recognition tests. Analysis of the ultrasonic vocalizations of pups following maternal separation revealed significant differences in call properties and vocal repertoire for Lnx1-/- and Lnx1-/-;Lnx2-/- double knockout animals. Finally, decreased body weight previously noted in double knockout animals could be attributed largely to Lnx1 gene knockout.

Conclusions: These results identify specific roles of LNX1 and LNX2 proteins in modulating distinct aspects of anxiety and risk-taking behaviour and social communication in mice. They also reveal an unexpected role for neuronally expressed LNX1 isoforms in determining body weight. These novel insights into the differential neuronal functions of LNX1 and LNX2 proteins provide a foundation for mechanistic studies of these phenomena.

行为学分析揭示了LNX1和LNX2在单敲除和双敲除小鼠中神经元功能的差异。
背景:NUMB蛋白- x1配体(LNX1)和LNX2蛋白是密切相关的含有PDZ结构域的E3泛素连接酶,它们与许多突触和神经发育重要的蛋白相互作用并可能调节。虽然lnnx1和LNX2都在神经元中表达,但值得注意的是,神经元中的lnnx1亚型缺乏负责底物泛素化的催化结构域。因此,LNX1和LNX2的共同相互作用伙伴可能受到这些蛋白的不同调控,其中LNX1作为稳定支架,而LNX2可能促进它们的泛素化和降解。尽管鉴定了许多LNX相互作用的蛋白和底物,但我们对LNX1和LNX2在体内不同功能的了解仍然非常不完整。结果:我们之前报道过中枢神经系统缺乏LNX1和LNX2的小鼠整体表现出焦虑相关行为的减少。在这里,我们通过首次检查Lnx1-/-和Lnx2-/-单基因敲除动物的焦虑相关行为和冒险行为,并通过分析单基因敲除和双基因敲除动物先前未探索的行为方面,显著扩展了这项工作。LNX1和LNX2的缺失有助于双基因敲除动物在开阔场地和高架迷宫测试中焦虑相关行为的减少,而LNX2的缺失在暗光涌现测试和钢丝梁桥冒险范式中的行为改变中发挥更显著的作用。相比之下,所有基因型Lnx敲除小鼠在大理石掩埋、应激性热疗和新物体识别测试中与野生型小鼠没有明显区别。对母鼠分离后幼崽超声发声的分析显示,Lnx1-/-和Lnx1-/-;Lnx2-/-双敲除动物的叫声特性和发声曲目存在显著差异。最后,先前在双敲除动物中发现的体重下降可能主要归因于Lnx1基因敲除。结论:这些结果确定了LNX1和LNX2蛋白在调节小鼠焦虑、冒险行为和社交的不同方面的特定作用。它们还揭示了神经元表达的LNX1异构体在决定体重方面的意想不到的作用。这些关于LNX1和LNX2蛋白神经元功能差异的新见解为这些现象的机制研究提供了基础。
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
Behavioral and Brain Functions
Behavioral and Brain Functions 医学-行为科学
CiteScore
5.90
自引率
0.00%
发文量
11
审稿时长
6-12 weeks
期刊介绍: A well-established journal in the field of behavioral and cognitive neuroscience, Behavioral and Brain Functions welcomes manuscripts which provide insight into the neurobiological mechanisms underlying behavior and brain function, or dysfunction. The journal gives priority to manuscripts that combine both neurobiology and behavior in a non-clinical manner.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信