The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

Ko, Jaewon

doi:10.1007/s10059-012-0113-3

Cited by 49 publications

(43 citation statements)

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“…The list of known synaptic CAMs has expanded rapidly, although the precise synaptic functions of most CAMs remain incompletely understood. Among the various CAMs, neuronal transmembrane proteins containing extracellular leucine-rich repeat (LRR) domains, in particular, have received considerable research attention (2)(3)(4).…”

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confidence: 99%

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

Yim

Kwon

Nam

et al. 2013

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

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The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit-and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.leucine-rich repeat | neuropsychiatic disorder | synaptic cell-adhesion

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confidence: 99%

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

Yim

Kwon

Nam

et al. 2013

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

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160

217

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“…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)(2)(3)(4). However, little is known about the specific pathophysiological mechanisms by which dysfunctions of synaptic adhesion molecules contribute to these complex disorders.…”

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confidence: 99%

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.

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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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“…Synaptic cell adhesion molecules (CAMs) are thought to regulate various stages of synapse formation including the initial contact between axons and dendrites, the formation and stabilization of early synapses and their differentiation into mature synapses (Dalva et al, 2007;Han and Kim, 2008;Südhof, 2008;Brose, 2009;Shen and Scheiffele, 2010;Williams et al, 2010;Siddiqui and Craig, 2011;Yuzaki, 2011;Ko, 2012). Recently, a large number of synaptic adhesion molecules have been identified, examples of which include neuroligins, neurexins, SynCAMs, LRRTMs, NGLs, SALMs, LAR-PTPs, TrkC, Cblns-GluRd, IL1RAPL1, IL1RAcP and Slitrks (Biederer et al, 2002;Lin et al, 2003;Kim et al, 2006;Ko et al, 2006;Wang et al, 2006;Südhof, 2008;de Wit et al, 2009;Ko et al, 2009;Linhoff et al, 2009;Woo et al, 2009b;Kwon et al, 2010;Matsuda et al, 2010;Siddiqui et al, 2010;Uemura et al, 2010;Takahashi et al, 2011;Valnegri et al, 2011;Yoshida et al, 2011;Takahashi et al, 2012;Yoshida et al, 2012;Yim et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

Song

Lee

Prosselkov

et al. 2013

Journal of Cell Science

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SummaryThe initial contact between axons and dendrites at early neuronal synapses is mediated by surface adhesion molecules and is thought to induce synaptic maturation through the recruitment of additional synaptic proteins. The initiation of synaptic maturation should be tightly regulated to ensure that synaptic maturation occurs selectively at subcellular sites of axo-dendritic adhesion. However, the underlying mechanism is poorly understood. Here, we report that the initial trans-synaptic adhesion mediated by presynaptic netrin-G1 and postsynaptic NGL-1 (netrin-G1 ligand-1) induces a cis interaction between netrin-G1 and the receptor protein tyrosine phosphatase LAR (leukocyte antigen-related), and that this promotes presynaptic differentiation. We propose that trans-synaptic adhesions at early neuronal synapses trigger recruitment of neighboring adhesion molecules in a cis manner in order to couple initial axo-dendritic adhesion with synaptic differentiation.

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The Leucine-Rich Repeat Superfamily of Synaptic Adhesion Molecules: LRRTMs and Slitrks

Cited by 49 publications

References 48 publications

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

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

Trans-induced cis interaction in the tripartite NGL-1, netrin-G1, and LAR adhesion complex promotes excitatory synaptic development

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