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Ror2 Functions As a Noncanonical Wnt Receptor That Regulates NMDAR-Mediated Synaptic Transmission

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Ror2 Functions As a Noncanonical Wnt Receptor That Regulates NMDAR-Mediated Synaptic Transmission RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission Waldo Cerpaa,1, Elena Latorre-Estevesa,b, and Andres Barriaa,2 aDepartment of Physiology and Biophysics and bMolecular and Cellular Biology Program, University of Washington, Seattle, WA 98195 Edited* by Richard L. Huganir, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved March 6, 2015 (received for review September 16, 2014) Wnt signaling has a well-established role as a regulator of nervous receptor for noncanonical Wnt ligands capable of regulating syn- system development, but its role in the maintenance and regula- aptic NMDARs. In hippocampal neurons, activation of RoR2 by tion of established synapses in the mature brain remains poorly noncanonical Wnt ligand Wnt5a activates PKC and JNK, two understood. At excitatory glutamatergic synapses, NMDA receptors kinases involved in the regulation of NMDAR currents. In ad- (NMDARs) have a fundamental role in synaptogenesis, synaptic dition, we show that signaling through RoR2 is necessary for plasticity, and learning and memory; however, it is not known what the maintenance of basal NMDAR-mediated synaptic trans- controls their number and subunit composition. Here we show that mission and the acute regulation of NMDAR synaptic responses the receptor tyrosine kinase-like orphan receptor 2 (RoR2) func- by Wnt5a. tions as a Wnt receptor required to maintain basal NMDAR- Identification of RoR2 as a Wnt receptor that regulates syn- aptic NMDARs provides a mechanism for Wnt signaling to mediated synaptic transmission. In addition, RoR2 activation by a control synaptic transmission and synaptic plasticity acutely, and noncanonical Wnt ligand activates PKC and JNK and acutely en- is a critical first step toward understanding the role played by hances NMDAR synaptic responses. Regulation of a key component Wnt signaling in the regulation of glutamatergic synaptic func- of glutamatergic synapses through RoR2 provides a mechanism for tion under normal or pathological conditions. Wnt signaling to modulate synaptic transmission, synaptic plasticity, and brain function acutely beyond embryonic development. Results RoR2 Receptor Is Expressed in Hippocampal Neurons of Juvenile NMDA receptors | Wnt signaling | synaptic transmission | RoR2 | Rodents. RoR2 receptors have been implicated in multiple as- glutamate receptors pects of brain development in Caenorhabditis elegans and Xenopus laevis, where they have been associated with Wnt5a signaling nt ligands are highly conserved secreted glycoproteins (18, 19). Although they have been detected in mammalian cul- Wresponsible for important developmental and homeostatic tured neurons (20), their function beyond embryonic develop- processes throughout the animal kingdom (1, 2). They play a key ment, i.e., in the regulation of established synaptic connections, role in morphogenesis, patterning, and lineage decision during is not known. In situ hybridization shows that RoR2 mRNA is highly expressed central and peripheral nervous system development (3). Wnt NEUROSCIENCE ligands control gene expression (4), and their dysregulation has in the cell body of CA1 and CA3 neurons in the mature hip- been implicated in cancer and major neuropathologies (5–9). pocampus of mice (Fig. 1A; Allen Mouse Brain Atlas [21]). The sustained expression of Wnt ligands and Wnt signaling RoR2 mRNA is also detected in juvenile rats by using total components in the mature mammalian CNS and their involve- mRNA isolated from hippocampi and RT-PCR (Fig. 1B). ment in neuropathologies suggest that these signaling cascades Immunostaining of 2-wk-old cultured rat hippocampal neurons might also play a part in synaptic maintenance and function confirmed the expression of RoR2 protein and its distribution beyond embryonic development (10, 11). However, because of throughout the cell body and dendrites (Fig. S1A). Subcellular the pleiotropy and complexity of Wnt signaling, it has been dif- fractionation shows that RoR2 is not enriched in a hippocampal ficult to dissect the components of Wnt signaling present in synaptosomal preparation (Fig. 1C and Fig. S1B). Consistent mature neurons and their role, if any, in the regulation of established synaptic connections and synaptic transmission. Significance Although most excitatory glutamatergic neurotransmission in the brain is mediated by AMPA-type glutamate receptors [i.e., AMPA NMDA receptors (NMDARs) are key components of excitatory receptors (AMPARs)], unique properties allow the NMDA-type synapses. Here we report that Wnt signaling via activation of glutamate receptors [i.e., NMDA receptors (NMDARs)] to play a tyrosine kinase-like orphan receptor 2 can regulate synaptic critical role in synaptic plasticity, learning and memory, and the – NMDARs. Understanding what controls number and subunit establishment and maturation of functional neural circuits (12 14). composition is central to understand neuropathologies associated Despite their importance, it is not known what controls the number with dysfunction of synaptic NMDARs, including Alzheimer’s and subunit composition of synaptic NMDARs. Dysfunction of NMDARs has been implicated in numerous diseases, including disease and schizophrenia. Our data indicate a previously un- Huntington disease, Parkinson disease, depression, bipolar disorder, identified role for Wnt signaling in the regulation of estab- and schizophrenia (14, 15), in which a deficit in NMDAR mediated lished synaptic connections and provides a mechanism for Wnt neurotransmission may be central (16). Interestingly, NMDAR- ligands to modulate basal synaptic transmission, synaptic plas- mediated currents can be acutely and specifically up-regulated ticity, and brain functions acutely. by Wnt5a, a noncanonical Wnt ligand (17), but little is known regarding the signaling pathway and mechanisms involved in Author contributions: W.C. and A.B. designed research; W.C., E.L.-E., and A.B. performed such regulation. research; W.C., E.L.-E., and A.B. analyzed data; and A.B. wrote the paper. The receptor tyrosine kinase-like orphan receptor 2 (RoR2) is The authors declare no conflict of interest. part of a conserved family of tyrosine kinase-like receptors that *This Direct Submission article had a prearranged editor. have been proposed to serve as a receptor for noncanonical Wnt 1Present address: Departamento de Biología Celular y Molecular, Facultad de Ciencias ligands, participating in developmental processes like cell move- Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile. ment and cell polarity (18, 19). Although RoR2 protein has been 2To whom correspondence should be addressed. Email: [email protected]. detected in mammalian neurons (20), its function and signaling This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. pathways are not known. Here we show that RoR2 acts as a 1073/pnas.1417053112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1417053112 PNAS | April 14, 2015 | vol. 112 | no. 15 | 4797–4802 Downloaded by guest on September 26, 2021 A B C portion of RoR2, resembles the Wnt binding site of the Frizzled Std RoR2 Actin HS P proteins (24) and binds to Wnt5a (19). In addition, a signaling- 500 400 RoR2 deficient mCherry-RoR2 was created by deleting most of the 300 intracellular carboxyl terminus (CT) that contains putative sig- 200 PSD95 naling domains (25) (Fig. 2A). Targeting of these recombinant Low High RoR2 receptors to dendrites was not altered (Fig. S2A). Organotypic hippocampal slices were transfected by using D E 0.4 0.3 biolistics with mCherry-RoR2 WT or deletion mutants. Trans- 0.2 ICQ fected CA1 pyramidal cells were identified and synaptic gluta- 0.1 matergic currents recorded in whole-cell configuration. Synaptic 0 responses were evoked by stimulation of the Schaffer collaterals with a bipolar electrode. The amplitude of synaptic responses were compared with responses evoked under the same con- F ditions in a nontransfected adjacent neuron (Fig. 2B,paired recordings). AMPAR-mediated responses were recorded at a RoR2 + PSD95 RoR2 + GluN2A holding potential of −60 mV. NMDAR-mediated responses RoR2 + Gephyrin RoR2 + GluN2B ABWT ΔCRD ΔCT Non- Transfected Fig. 1. Expression of RoR2 receptor in juvenile hippocampus. (A) In situ Transfected hybridization for RoR2 in hippocampus from the Allen Mouse Brain Atlas mCherry (mouse.brain-map.org/) (21). Pseudocolor indicates level of expression. C RD (B) Reverse transcription reaction from total rat hippocampus mRNA and PCR using specific primers for rat RoR2 or β-actin. (C) Representative immunoblot Tyr Kinase Like D PRD of RoR2 and PSD95 in a synaptosomal preparation (marked as “P”), super- S/T RD natant (marked as “S”), or total homogenate (marked as “H”). (D) Repre- CDENMDAR EPSCs AMPAR EPSCs NMDARs AMPARs sentative images of dendrites from neurons expressing GFP and mCherry- * μ μ 1.5 RoR2. (Scale bars: Left,5 m; Center and Right,2 m.) (E) Quantification of 150 150 colocalization of endogenous RoR2 and synaptic markers. ICQ (22) for RoR2 1 and PSD95, RoR2 and GluN2A, RoR2 and GluN2B, and RoR2 and gephyrin 100 100 (stripped bars; n = 22, n = 15, n = 8, and n = 15, respectively). The experi- 50 50 0.5 mental maximum ICQ value is given by the pair mCherry-GluN2A and GFP- RoR2 WT Amplitude (pA) GluN2A (black bar; n = 4), whereas the minimum is given by the pair GluN2A 0 0 EPSC Amplitude 0 and gephyrin (white bar; n = 9). (F) Representative images of dendrites 050100150 050100150 CtrlRoR2
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