title: Soluble LILRA3 promotes neurite outgrowth and synapses formation through a high-affinity interaction with Nogo 66.
abstract: Inhibitory proteins, particularly Nogo 66, a highly conserved 66-amino-acid loop of Nogo A (an isoform of RTN4), play key roles in limiting the intrinsic capacity of the central nervous system (CNS) to regenerate after injury. Ligation of surface Nogo receptors (NgRs) and/or leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue the paired immunoglobulin-like receptor B (PIRB) by Nogo 66 transduces inhibitory signals that potently inhibit neurite outgrowth. Here, we show that soluble leukocyte immunoglobulin-like receptor A3 (LILRA3) is a high-affinity receptor for Nogo 66, suggesting that LILRA3 might be a competitive antagonist to these cell surface inhibitory receptors. Consistent with this, LILRA3 significantly reversed Nogo-66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons through regulation of the ERK/MEK pathway. LILRA3 represents a new antagonist to Nogo-66-mediated inhibition of neurite outgrowth in the CNS, a function distinct from its immune-regulatory role in leukocytes. This report is also the first to demonstrate that a member of LILR family normally not expressed in rodents exerts functions on mouse neurons through the highly homologous Nogo 66 ligand.
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Department of Pathology, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Hongyan
authors.initials: H
authors.lastname: An
authors.affiliation: Neurodegeneration and Repair Unit, School of Medical Sciences, Department of Anatomy, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Merryn
authors.initials: M
authors.lastname: Brettle
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Department of Pathology, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Terry
authors.initials: T
authors.lastname: Lee
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, 2109, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Heng
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, 2109, Australia.
authors.forename: Chai K
authors.initials: CK
authors.lastname: Lim
authors.affiliation: Faculty of Medicine and Health Sciences, Department of Biomedical Sciences, Macquarie University, Sydney, 2109, Australia.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: Graduate School of Biomedical Engineering, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lord
authors.affiliation: EMBL Australia Node in Single Molecule Science, School of Medical Sciences, ARC Centre of Excellence in Advanced Molecular Imaging, The University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Enrico
authors.initials: E
authors.lastname: Klotzsch
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Department of Pathology, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Geczy
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Department of Pathology, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Bryant
authors.affiliation: Neurodegeneration and Repair Unit, School of Medical Sciences, Department of Anatomy, UNSW, Sydney, New South Wales 2052, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fath
authors.affiliation: Inflammation and Infection Research Centre, School of Medical Sciences, Department of Pathology, UNSW, Sydney, New South Wales 2052, Australia n.tedla@unsw.edu.au.
authors.forename: Nicodemus
authors.initials: N
authors.lastname: Tedla
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis; D000071446:Neuronal Outgrowth; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D000070798:Nogo Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: C530062:LILRA3 protein, human; D000070798:Nogo Proteins; D011971:Receptors, Immunologic
keywords: Cortical neuron; Leukocyte immunoglobulin-like receptor A3; Neurite outgrowth; Nogo 66; PIRB; Synapse