Decreased anxiety-related behaviour but apparently unperturbed NUMB function in ligand of NUMB protein-X (LNX) 1/2 double knockout mice

dc.contributor.authorLenihan, Joan A.
dc.contributor.authorSaha, Orthis
dc.contributor.authorHeimer-McGinn, Victoria
dc.contributor.authorCryan, John F.
dc.contributor.authorFeng, Guoping
dc.contributor.authorYoung, Paul W.
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderIrish Research Councilen
dc.date.accessioned2017-01-24T09:21:00Z
dc.date.available2017-01-24T09:21:00Z
dc.date.issued2016-11-26
dc.date.updated2017-01-23T13:47:42Z
dc.description.abstractNUMB is a key regulator of neurogenesis and neuronal differentiation that can be ubiquitinated and targeted for proteasomal degradation by ligand of numb protein-X (LNX) family E3 ubiquitin ligases. However, our understanding of LNX protein function in vivo is very limited. To examine the role of LNX proteins in regulating NUMB function in vivo, we generated mice lacking both LNX1 and LNX2 expression in the brain. Surprisingly, these mice are healthy, exhibit unaltered levels of NUMB protein and do not display any neuroanatomical defects indicative of aberrant NUMB function. Behavioural analysis of LNX1/LNX2 double knockout mice revealed decreased anxiety-related behaviour, as assessed in the open field and elevated plus maze paradigms. By contrast, no major defects in learning, motor or sensory function were observed. Given the apparent absence of major NUMB dysfunction in LNX null animals, we performed a proteomic analysis to identify neuronal LNX-interacting proteins other than NUMB that might contribute to the anxiolytic phenotype observed. We identified and/or confirmed interactions of LNX1 and LNX2 with proteins known to have presynaptic and neuronal signalling functions, including the presynaptic active zone constituents ERC1, ERC2 and LIPRIN-αs (PPFIA1, PPFIA3), as well as the F-BAR domain proteins FCHSD2 (nervous wreck homologue) and SRGAP2. These and other novel LNX-interacting proteins identified are promising candidates to mediate LNX functions in the central nervous system, including their role in modulating anxiety-related behaviour.en
dc.description.sponsorshipScience Foundation Ireland (Research Frontiers Programme grant 08/RFP/ NSC1382); Irish Research Council (EMBARK Postgraduate Research Scholarship)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLenihan, J. A., Saha, O., Heimer-McGinn, V., Cryan, J. F., Feng, G. and Young, P. W. (2016) 'Decreased anxiety-related behaviour but apparently unperturbed NUMB function in ligand of NUMB protein-X (LNX) 1/2 double knockout mice', Molecular Neurobiology, 54(10), pp. 8090-8109. doi:10.1007/s12035-016-0261-0en
dc.identifier.doi10.1007/s12035-016-0261-0
dc.identifier.endpage8109
dc.identifier.issn0893-7648
dc.identifier.issued10
dc.identifier.journaltitleMolecular Neurobiologyen
dc.identifier.startpage8090
dc.identifier.urihttps://hdl.handle.net/10468/3505
dc.identifier.volume54
dc.language.isoenen
dc.publisherSpringer Science+Business Mediaen
dc.rights© 2016, Springer Science+Business Media New York. The final publication is available at Springer via http://dx.doi.org/ 10.1007/s12035-016-0261-0en
dc.subjectLNX1en
dc.subjectLNX2en
dc.subjectLIPRIN/PPFIAen
dc.subjectERC1/ERC2en
dc.subjectNUMBen
dc.subjectAnxietyen
dc.titleDecreased anxiety-related behaviour but apparently unperturbed NUMB function in ligand of NUMB protein-X (LNX) 1/2 double knockout miceen
dc.typeArticle (peer-reviewed)en
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