title: RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission.
abstract: Wnt signaling has a well-established role as a regulator of nervous system development, but its role in the maintenance and regulation of established synapses in the mature brain remains poorly understood. At excitatory glutamatergic synapses, NMDA receptors (NMDARs) have a fundamental role in synaptogenesis, synaptic plasticity, and learning and memory; however, it is not known what controls their number and subunit composition. Here we show that the receptor tyrosine kinase-like orphan receptor 2 (RoR2) functions as a Wnt receptor required to maintain basal NMDAR-mediated synaptic transmission. In addition, RoR2 activation by a noncanonical Wnt ligand activates PKC and JNK and acutely enhances NMDAR synaptic responses. Regulation of a key component of glutamatergic synapses through RoR2 provides a mechanism for Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development.
authors.affiliation: Department of Physiology and Biophysics and.
authors.forename: Waldo
authors.initials: W
authors.lastname: Cerpa
authors.affiliation: Department of Physiology and Biophysics and Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195.
authors.forename: Elena
authors.initials: E
authors.lastname: Latorre-Esteves
authors.affiliation: Department of Physiology and Biophysics and barria@uw.edu.
authors.forename: Andres
authors.initials: A
authors.lastname: Barria
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D015870:Gene Expression; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018613:Microscopy, Confocal; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D051381:Rats; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D009435:Synaptic Transmission; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C500913:Ror2 protein, rat; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases
keywords: NMDA receptors; RoR2; Wnt signaling; glutamate receptors; synaptic transmission
references.citation: Nat Neurosci. 2001 Apr;4(4):382-90
references.pmid: 11276228
references.citation: Nat Rev Neurosci. 2010 Feb;11(2):77-86
references.pmid: 20010950
references.citation: Trends Pharmacol Sci. 2003 May;24(5):233-8
references.pmid: 12767722
references.citation: J Cell Biol. 2003 Jun 9;161(5):899-909
references.pmid: 12782683
references.citation: Genes Cells. 2003 Jul;8(7):645-54
references.pmid: 12839624
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:318-27
references.pmid: 14684455
references.citation: Nat Genet. 2004 Feb;36(2):131-7
references.pmid: 14745448
references.citation: J Neurosci. 2004 Apr 21;24(16):4070-81
references.pmid: 15102922
references.citation: Annu Rev Cell Dev Biol. 2004;20:781-810
references.pmid: 15473860
references.citation: Curr Biol. 1998 Jun 4;8(12):R407
references.pmid: 9637909
references.citation: J Cell Sci. 2005 Jan 15;118(Pt 2):433-46
references.pmid: 15654020
references.citation: Nat Rev Neurosci. 2005 May;6(5):351-62
references.pmid: 15832199
references.citation: Cell Mol Life Sci. 2005 May;62(10):1100-8
references.pmid: 15928805
references.citation: Neuron. 2005 Oct 20;48(2):289-301
references.pmid: 16242409
references.citation: J Biol Chem. 2006 Aug 11;281(32):22429-33
references.pmid: 16793760
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18769-74
references.pmid: 17124177
references.citation: Nature. 2007 Jan 11;445(7124):168-76
references.pmid: 17151600
references.citation: Curr Opin Genet Dev. 2007 Feb;17(1):45-51
references.pmid: 17208432
references.citation: Nat Rev Neurosci. 2007 Jun;8(6):413-26
references.pmid: 17514195
references.citation: Proc Natl Acad Sci U S A. 2007 May 29;104(22):9434-9
references.pmid: 17517621
references.citation: J Physiol. 2008 Mar 15;586(6):1509-17
references.pmid: 18202093
references.citation: PLoS One. 2008;3(3):e1873
references.pmid: 18365018
references.citation: Arch Gen Psychiatry. 2008 Jul;65(7):785-93
references.pmid: 18606951
references.citation: Trends Cell Biol. 2008 Nov;18(11):536-44
references.pmid: 18848778
references.citation: J Vis Exp. 2008;(12). pii: 675. doi: 10.3791/675
references.pmid: 19066564
references.citation: Cell. 2009 Mar 20;136(6):1017-31
references.pmid: 19303846
references.citation: J Biol Chem. 2009 Jun 5;284(23):15857-66
references.pmid: 19332546
references.citation: Nat Rev Mol Cell Biol. 2009 Jul;10(7):468-77
references.pmid: 19536106
references.citation: Development. 2009 Oct;136(19):3205-14
references.pmid: 19736321
references.citation: J Neurosci. 2010 Jan 6;30(1):242-54
references.pmid: 20053906
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5459-64
references.pmid: 20212108
references.citation: J Neurophysiol. 2011 Jan;105(1):162-71
references.pmid: 20980539
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5855-60
references.pmid: 21427228
references.citation: J Neurosci. 2011 Jun 29;31(26):9466-71
references.pmid: 21715611
references.citation: PLoS One. 2012;7(10):e46683
references.pmid: 23071613
references.citation: Nat Rev Neurosci. 2013 Jun;14(6):383-400
references.pmid: 23686171
references.citation: Neuropharmacology. 2013 Nov;74:32-40
references.pmid: 23628345
references.citation: Neuron. 2002 Jul 18;35(2):345-53
references.pmid: 12160751