Silencing of Neuroligin Function by Postsynaptic Neurexins

Taniguchi, Hiroki; Gollan, Leora; Scholl, Francisco G.; Mahadomrongkul, Veeravan; Dobler, Elizabeth; Limthong, Nicolas; Peck, Morgen; Aoki, Chiye; Scheiffele, Peter

doi:10.1523/jneurosci.0032-07.2007

Cited by 130 publications

(127 citation statements)

References 40 publications

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“…Coexpression of MDGA1 or of Nrx1β with NL2 in HEK293T cells in a cis configuration strongly impaired the synaptogenic activity of NL2 (Fig. 5 A and B), as reported previously for Nrx1β (32). In contrast, cis expression of MDGA1 with NL1 did not affect the synaptogenic activity of NL1, consistent with the observation that MDGA1 does not interact with NL1 ( Figs.…”

Section: Overexpression Of Mdga1 Decreases Inhibitory Synaptic Transmsupporting

confidence: 91%

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

Lee

Kim

Lee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

139

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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.inhibitory synapse formation | synaptic cell adhesion | autism | schizophrenia R ecent studies of synapse formation have uncovered a multitude of synaptic adhesion molecules, and human genetic studies have implicated many of these molecules in neuropsychiatric and neurodevelopmental disorders (1-4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.Neurexins and neuroligins (NLs) are arguably the most extensively studied synaptic adhesion molecules (1). They are dispensable for initial synapse establishment but act in an isoformdependent manner to specify the maturation of either excitatory or inhibitory synapses (5). There are four NL members in rodents (NL1-NL4) that show distinct synaptic localizations and functions (5). NL2, in particular, has received considerable attention because of its unique localization and function at inhibitory synapses (6). For instance, NL2 controls perisomatic inhibitory synapse maturation together with gephyrin and collybistin, which regulate GABA receptor clustering on neurons (7,8). Moreover, NL2 exhibits differential functions at different types of inhibitory synapses on the same postsynaptic neuron (9). All four NLs likely mediate synapse-promoting activities through direct interactions with presynaptic neurexins, but NLs also perform additional functions in synapse validation that are independent of their binding to neurexins (10).MAM domain-containing GPI anchor proteins (MDGAs), also termed "GPIMs" or "MAMDCs," initially were identified in tumor cells (11). The two homologous MDGA ...

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Section: Overexpression Of Mdga1 Decreases Inhibitory Synaptic Transmsupporting

confidence: 91%

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

Lee

Kim

Lee³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

111

139

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“…However, such analyses of Syn-CAM complex assembly will have to await the ultrastructural subsynaptic localization of each SynCAM family member, and determining the extent of their presynaptic versus postsynaptic localization will provide insight into the structure and function of SynCAM complexes. Although SynCAMs are found at both presynaptic and postsynaptic membranes (Biederer et al, 2002), lateral cis-interactions may occur in addition to the binding of SynCAMs in trans-interactions, which could serve to regulate their transsynaptic interactions similar as described previously for neurexins and neuroligins (Taniguchi et al, 2007) and for cadherin-mediated adhesion (Tanaka et al, 2000). With respect to transsynaptic functions of SynCAM complexes, it is notable that neurexins also are found at both presynaptic and postsynaptic membranes (Taniguchi et al, 2007).…”

mentioning

confidence: 72%

“…A different small family of synaptic adhesion molecules was identified in vertebrates with the purification of neurexins (Ushkaryov et al, 1992;Ushkaryov and Südhof, 1993) and their postsynaptic partners, neuroligins (Ichtchenko et al, 1995;Boucard et al, 2005). Neuroligins were shown to interact with neurexins to control the number of functional presynaptic terminals (Scheiffele et al, 2000;Dean et al, 2003;Levinson et al, 2005;Taniguchi et al, 2007). Conversely, neurexins cause postsynaptic protein assembly through binding of neuroligins (Graf et al, 2004;Chih et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

SynCAMs Organize Synapses through Heterophilic Adhesion

Fogel¹,

Akins²,

Krupp³

et al. 2007

J. Neurosci.

184

278

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Synapses are asymmetric cell junctions with precisely juxtaposed presynaptic and postsynaptic sides. Transsynaptic adhesion complexes are thought to organize developing synapses. The molecular composition of these complexes, however, remains incompletely understood, precluding us from understanding how adhesion across the synaptic cleft guides synapse development. Here, we define two immunoglobulin superfamily members, SynCAM 1 and 2, that are expressed in neurons in the developing brain and localize to excitatory and inhibitory synapses. They function as cell adhesion molecules and assemble with each other across the synaptic cleft into a specific, transsynaptic SynCAM 1/2 complex. Additionally, SynCAM 1 and 2 promote functional synapses as they increase the number of active presynaptic terminals and enhance excitatory neurotransmission. The interaction of SynCAM 1 and 2 is affected by glycosylation, indicating regulation of this adhesion complex by posttranslational modification. The SynCAM 1/2 complex is representative for the highly defined adhesive patterns of this protein family, the four members of which are expressed in neurons in divergent expression profiles. SynCAMs 1, 2, and 3 each can bind themselves, yet preferentially assemble into specific, heterophilic complexes as shown for the synaptic SynCAM 1/2 interaction and a second complex comprising SynCAM 3 and 4. Our results define SynCAM proteins as components of novel heterophilic transsynaptic adhesion complexes that set up asymmetric interactions, with SynCAM proteins contributing to synapse organization and function.

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“…This interaction prevents the formation of trans axonin-1/axonin-1 associations (60,61), and enhances neurite fasciculation (60,62). Another example of cis interactions regulating trans associations includes the neurexins, which were recently reported to be postsynaptic, in addition to being presynaptic (63). When postsynaptic neurexins form cis complexes with postsynaptic neuroligin-1, the interaction inhibits the ability of neuroligin-1 to interact with presynaptic neurexins (63).…”

Section: Discussionmentioning

confidence: 99%

“…Another example of cis interactions regulating trans associations includes the neurexins, which were recently reported to be postsynaptic, in addition to being presynaptic (63). When postsynaptic neurexins form cis complexes with postsynaptic neuroligin-1, the interaction inhibits the ability of neuroligin-1 to interact with presynaptic neurexins (63). Therefore, SALM4 and SALM5 trans-cellular interactions may also be influenced and regulated by their cis interactions with other SALM family members, and vice versa, similar to other cell adhesion molecules.…”

Section: Discussionmentioning

confidence: 99%

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

Seabold

Wang

Chang

et al. 2008

Journal of Biological Chemistry

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Synaptic adhesion-like molecules (SALMs) are a newly discovered family of adhesion molecules that play roles in synapse formation and neurite outgrowth. The SALM family is comprised of five homologous molecules that are expressed largely in the central nervous system. SALMs 1-3 contain PDZ-binding domains, whereas SALMs 4 and 5 do not. We are interested in characterizing the interactions of the SALMs both among the individual members and with other binding partners. In the present study, we focused on the interactions formed by the five SALM members in rat brain and heterologous cells. In brain, we found that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4 and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes. In heterologous cells transfected with SALMs, co-immunoprecipitation studies showed that all five SALMs form heteromeric and homomeric complexes. We also determined if SALMs could form trans-cellular associations between transfected heterologous cells. Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. The ability of SALM4 to form trans interactions is due to its extracellular N terminus because chimeras of SALM4 N terminus and SALM2 C terminus can form trans interactions, whereas chimeras of SALM2 N terminus and SALM4 C terminus cannot. Co-culture experiments using HeLa cells and rat hippocampal neurons expressing the SALMs showed that SALM4 is recruited to points of contact between the cells. In neurons, these points of contact were seen in both axons and dendrites.Critical steps in the development of the nervous system, including cell migration, neurite outgrowth, growth cone guidance, and synapse formation, depend on cellular interactions mediated by adhesion molecules (1-4). A number of adhesion molecules that are essential to the proper development of the nervous system have been identified (5-7). The importance of these molecules is illustrated in cases of dysfunctional adhesion molecules that have been associated with specific disorders in humans, including SLITRK1 in Tourette syndrome (8) and neuroligin in autism (9, 10). Whereas our understanding of the role of adhesion molecules in neuronal development is rapidly increasing, little is known about their functions, and it is likely that many remain to be identified.Synaptic adhesion-like molecules (SALMs) 2 are a recently identified class of adhesion molecules that are highly enriched in brain (11-13). All five members of the SALM family contain extracellular leucine-rich repeats (LRR), an immunoglobulin C2-like (IgC2) domain, a fibronectin type III (FNIII) domain, a transmembrane domain, and a cytoplasmic C-terminal tail. SALMs 1-3 contain a C-terminal PDZ-binding domain (PDZ-BD), which associates with the PSD-95 family of proteins (11-13). SALMs are expressed early in the developing nervous system and persist into adulthood. They are present at the synaptic membrane as well as at non-synaptic locations. SALM1 overe...

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Silencing of Neuroligin Function by Postsynaptic Neurexins

Cited by 130 publications

References 40 publications

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

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

SynCAMs Organize Synapses through Heterophilic Adhesion

The SALM Family of Adhesion-like Molecules Forms Heteromeric and Homomeric Complexes

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