MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development

Kangduk Lee, Yoonji Kima, Sung Jin Lee, Yuan Qiang, Dongmin Lee, Hyun Woo Lee, Hyun Kim, H. Shawn Je, Thomas C. Südhof, Jaewon Ko

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

The MAM domain-containing GPI anchor proteins MDGA1 and MDGA2 are Ig superfamily adhesion molecules composed of six IG domains, a fibronectin III domain, a MAM domain, and a GPI anchor. MDGAs contribute to the radial migration and positioning of a subset of cortical neurons during early neural development. However, MDGAs continue to be expressed in postnatal brain, and their functions during postnatal neural development remain unknown. Here, we demonstrate that MDGAs specifically and with a nanomolar affinity bind to neuroligin-2, a cell-adhesion molecule of inhibitory synapses, but do not bind detectably to neuroligin-1 or neuroligin-3. We observed no cell adhesion between cells expressing neuroligin-2 and MDGA1, suggesting a cis interaction. Importantly, RNAi-mediated knockdown of MDGAs increased the abundance of inhibitory but not excitatory synapses in a neuroligin-2- dependent manner. Conversely, overexpression of MDGA1 decreased the numbers of functional inhibitory synapses. Likewise, coexpression of both MDGA1 and neuroligin-2 reduced the synaptogenic capacity of neuroligin-2 in an artificial synapse-formation assay by abolishing the ability of neuroligin-2 to form an adhesion complex with neurexins. Taken together, our data suggest that MDGAs inhibit the activity of neuroligin-2 in controlling the function of inhibitory synapses and that MDGAs do so by binding to neuroligin-2.

Original languageEnglish
Pages (from-to)336-341
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number1
DOIs
Publication statusPublished - 2013 Jan 2

Keywords

  • Autism
  • Inhibitory synapse formation
  • Schizophrenia
  • Synaptic cell adhesion

ASJC Scopus subject areas

  • General

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