title: Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice.
abstract: NUMB 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.
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Joan A
authors.initials: JA
authors.lastname: Lenihan
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.|Institut de Biologie de l'ENS (IBENS), INSERM, CNRS, École Normale Supérieure, PSL Research University, 75005, Paris, France.
authors.forename: Orthis
authors.initials: O
authors.lastname: Saha
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.|Department of Cognitive, Linguistic and Psychological Sciences, Brown University, Providence, RI, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Heimer-McGinn
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.|Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.|Cork Neuroscience Centre, University College Cork, Cork, Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.|Key Laboratory of Brain Functional Genomics (Ministry of Education and Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitive Science, East China Normal University, Shanghai, 200062, China.|Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, 02142, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland. p.young@ucc.ie.|Cork Neuroscience Centre, University College Cork, Cork, Ireland. p.young@ucc.ie.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Young
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics*; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D040901:Proteomics; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C454301:Lnx2 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D025801:Ubiquitin; C111865:Lnx1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Anxiety; ERC1/ERC2; LIPRIN/PPFIA; LNX1; LNX2; NUMB