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

Joris DeWit*, Matthew L. O'Sullivan, Jeffrey N. Savas, Giuseppe Condomitti, Max C. Caccese, Kristel M. Vennekens, John R. Yates, Anirvan Ghosh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

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 unbiasedproteomics-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 anHS-dependent manner. LRRTM4 positively regulates excitatory synapse development in cultured neurons and invivo, 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

Original languageEnglish (US)
Pages (from-to)696-711
Number of pages16
JournalNeuron
Volume79
Issue number4
DOIs
StatePublished - Aug 21 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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