Unbiased discovery of glypican as a receptor for LRRTM4 in regulating excitatory synapse development

Neuron. 2013 Aug 21;79(4):696-711. doi: 10.1016/j.neuron.2013.06.049. Epub 2013 Aug 1.


Leucine-rich repeat (LRR) proteins have recently been identified as important regulators of synapse development and function, but for many LRR proteins the ligand-receptor interactions are not known. Here we identify the heparan sulfate (HS) proteoglycan glypican as a receptor for LRRTM4 using an unbiased proteomics-based approach. Glypican binds LRRTM4, but not LRRTM2, in an HS-dependent manner. Glypican 4 (GPC4) and LRRTM4 localize to the pre- and postsynaptic membranes of excitatory synapses, respectively. Consistent with a trans-synaptic interaction, LRRTM4 triggers GPC4 clustering in contacting axons and GPC4 induces clustering of LRRTM4 in contacting dendrites in an HS-dependent manner. LRRTM4 positively regulates excitatory synapse development in cultured neurons and in vivo, and the synaptogenic activity of LRRTM4 requires the presence of HS on the neuronal surface. Our results identify glypican as an LRRTM4 receptor and indicate that a trans-synaptic glypican-LRRTM4 interaction regulates excitatory synapse development.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • Female
  • Glypicans / genetics
  • Glypicans / metabolism*
  • Hippocampus* / cytology
  • Hippocampus* / embryology
  • Hippocampus* / growth & development
  • Humans
  • In Vitro Techniques
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Molecular
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / physiology*
  • Pregnancy
  • Protein Binding / genetics
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Long-Evans
  • Synapses / metabolism
  • Synapses / physiology*


  • Glypicans
  • LRRN4 protein, human
  • Luminescent Proteins
  • Nerve Tissue Proteins
  • Protein Isoforms