RoR2 functions as a noncanonical Wnt receptor that regulates NMDAR-mediated synaptic transmission

Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):4797-802. doi: 10.1073/pnas.1417053112. Epub 2015 Mar 30.


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.

Keywords: NMDA receptors; RoR2; Wnt signaling; glutamate receptors; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Cells, Cultured
  • Gene Expression
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • In Situ Hybridization
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Microscopy, Confocal
  • Patch-Clamp Techniques
  • Protein Kinase C / metabolism
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology
  • RNA Interference
  • Rats
  • Receptor Tyrosine Kinase-like Orphan Receptors / genetics
  • Receptor Tyrosine Kinase-like Orphan Receptors / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Synaptic Transmission*
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt-5a Protein


  • Receptors, N-Methyl-D-Aspartate
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt5a protein, rat
  • Receptor Tyrosine Kinase-like Orphan Receptors
  • Ror2 protein, rat
  • Protein Kinase C
  • JNK Mitogen-Activated Protein Kinases