LGI1 is a Nogo receptor 1 ligand that antagonizes myelin-based growth inhibition.
Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features. LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22.
Thomas
Rhalena
R
Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montréal, Quebec H3A 2B4, Canada.
Favell
Kristy
K
Morante-Redolat
Jose
J
Pool
Madeline
M
Kent
Christopher
C
Wright
Melissa
M
Daignault
Kathleen
K
Ferraro
Gino B
GB
Montcalm
Samuel
S
Durocher
Yves
Y
Fournier
Alyson
A
Perez-Tur
Jordi
J
Barker
Philip A
PA
D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000502:physiology; D019556:COS Cells; D049108:Cell Enlargement; D002460:Cell Line; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000254:growth & development / Q000502:physiology; D020439:Growth Cones / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009185:Myelin Proteins / Q000378:metabolism*; D009186:Myelin Sheath / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*
D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; C513865:Lgi1 protein, rat; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; D000070816:Nogo Receptor 1; D011506:Proteins; C000603199:RTN4 protein, human; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface; C000603197:Rtn4 protein, rat; C486581:Rtn4r protein, rat; C513864:Adam22 protein, rat; D051722:ADAM Proteins; C498474:ADAM22 protein, human
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20476-81
19915139
Science. 1993 Jan 1;259(5091):77-9
8418498
Science. 2006 Sep 22;313(5794):1792-5
16990550
J Neurosci. 2004 Nov 17;24(46):10511-20
15548666
Epilepsy Res. 2008 Jul;80(1):1-8
18440780
J Neurosci. 2009 May 13;29(19):6285-95
19439606
J Neurosci. 2009 May 13;29(19):6348-52
19439611
Nat Genet. 2002 Mar;30(3):335-41
11810107
Hum Mol Genet. 2002 May 1;11(9):1119-28
11978770
J Neurosci. 2008 Mar 12;28(11):2753-65
18337405
Science. 2002 Aug 16;297(5584):1190-3
12089450
Mol Cell Neurosci. 2009 Dec;42(4):448-57
19796686
Neuron. 2006 Mar 2;49(5):697-706
16504945
Int J Biol Sci. 2008;4(6):387-96
18974846
Hum Mol Genet. 2005 Jun 15;14(12):1613-20
15857855
Nat Med. 2009 Oct;15(10):1208-14
19701204
Nucleic Acids Res. 2002 Jan 15;30(2):E9
11788735
Mamm Genome. 2007 May;18(5):328-37
17565425
J Neurosci. 2005 Jan 26;25(4):808-22
15673660
J Biol Chem. 2008 May 9;283(19):12709-16
18299325
J Neurosci. 2007 Jul 4;27(27):7117-24
17611264
Methods Enzymol. 2000;327:198-210
11044984
Nature. 2000 Jan 27;403(6768):439-44
10667797
Hum Mol Genet. 2006 Dec 1;15(23):3436-45
17067999
Curr Neurovasc Res. 2004 Jan;1(1):61-75
16181067
Nature. 2001 Jan 18;409(6818):341-6
11201742
BMC Genomics. 2007 Sep 14;8:320
17868438
Nature. 2002 May 30;417(6888):547-51
12037567
Science. 2005 Sep 30;309(5744):2222-6
16195464
Science. 2008 Nov 7;322(5903):967-70
18988857
J Mol Neurosci. 2008 Jul;35(3):323-9
18563303
J Neurosci. 2003 Feb 15;23(4):1416-23
12598630