title: MDGAs interact selectively with neuroligin-2 but not other neuroligins to regulate inhibitory synapse development.
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.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology,  Yonsei University, Seoul 120-749,  Korea.
authors.forename: Kangduk
authors.initials: K
authors.lastname: Lee
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Kim
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qiang
authors.forename: Dongmin
authors.initials: D
authors.lastname: Lee
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.forename: H Shawn
authors.initials: HS
authors.lastname: Je
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D058851:GPI-Linked Proteins / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D015151:Immunoblotting; D007136:Immunoglobulins / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules; D009474:Neurons / Q000166:cytology*; D034622:RNA Interference; D051381:Rats; D013569:Synapses / Q000502:physiology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; D058851:GPI-Linked Proteins; D007136:Immunoglobulins; C486864:MDGA1 protein, rat; C486865:MDGA2 protein, rat; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C098003:neuroligin 2