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

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dc.contributor.authorCioccarelli, Lauraen
dc.contributor.authorLenihan, Joan A.en
dc.contributor.authorErwin, Leah G.en
dc.contributor.authorYoung, Paul W.en
dc.contributor.funderResearch Irelanden
dc.contributor.funderLillyen
dc.date.accessioned2025-05-13T08:54:19Z
dc.date.available2025-05-13T08:54:19Z
dc.date.issued2025en
dc.description.abstractBackground: 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.en
dc.description.sponsorshipResearch Ireland (20/FFP-P/8767); Lilly (Research Scholarship)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid13en
dc.identifier.citationCioccarelli, L., Lenihan, J. A., Erwin, L. G. and Young, P. W. (2025) 'Differential neuronal functions of LNX1 and LNX2 revealed by behavioural analysis in single and double knockout mice', Behavioral and Brain Functions, 21(1), pp.1-16. https://doi.org/10.1186/s12993-025-00276-zen
dc.identifier.doi10.1186/s12993-025-00276-zen
dc.identifier.issn17449081en
dc.identifier.issued1
dc.identifier.journaltitleBehavioral and Brain Functionsen
dc.identifier.urihttps://hdl.handle.net/10468/17436
dc.identifier.volume21
dc.language.isoenen
dc.publisherBioMed Central Ltden
dc.relation.project20/FFP-P/8767en
dc.rights© 2025, the Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnxietyen
dc.subjectBody weighten
dc.subjectLNX1en
dc.subjectLNX2en
dc.subjectNUMBen
dc.subjectPDZ domainen
dc.subjectRisk-takingen
dc.subjectUbiquitin ligaseen
dc.titleDifferential neuronal functions of LNX1 and LNX2 revealed by behavioural analysis in single and double knockout miceen
dc.typeArticle (peer reviewed)en
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