A Splice Code for trans-Synaptic Cell Adhesion Mediated by Binding of Neuroligin 1 to α- and β-Neurexins

Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard NA4.118, Dallas, Texas 75390, USA.
Neuron (Impact Factor: 15.05). 11/2005; 48(2):229-36. DOI: 10.1016/j.neuron.2005.08.026
Source: PubMed


Previous studies suggested that postsynaptic neuroligins form a trans-synaptic complex with presynaptic beta-neurexins, but not with presynaptic alpha-neurexins. Unexpectedly, we now find that neuroligins also bind alpha-neurexins and that alpha- and beta-neurexin binding by neuroligin 1 is regulated by alternative splicing of neuroligin 1 (at splice site B) and of neurexins (at splice site 4). In neuroligin 1, splice site B is a master switch that determines alpha-neurexin binding but leaves beta-neurexin binding largely unaffected, whereas alternative splicing of neurexins modulates neuroligin binding. Moreover, neuroligin 1 splice variants with distinct neurexin binding properties differentially regulate synaptogenesis: neuroligin 1 that binds only beta-neurexins potently stimulates synapse formation, whereas neuroligin 1 that binds to both alpha- and beta-neurexins more effectively promotes synapse expansion. These findings suggest that neuroligin binding to alpha- and beta-neurexins mediates trans-synaptic cell adhesion but has distinct effects on synapse formation, indicating that expression of different neuroligin and neurexin isoforms specifies a trans-synaptic signaling code.

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Available from: Antony A Boucard, Oct 08, 2015
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    • "In contrast, NL2 and NL3 KOs caused selective impairments in subsets of GABAergic synapses (Chubykin et al., 2007; Gibson et al., 2009; Poulopoulos et al., 2009; Etherton et al., 2011; Fö ldy et al., 2013; Rothwell et al., 2014). Overexpression of all neuroligin isoforms, conversely, increased synapse numbers as assessed morphologically (Boucard et al., 2005; Chih et al., 2005; Ko et al., 2009b; Sara et al., 2005; Zhang et al., 2009). In addition, overexpression of NL1 enhanced both NMDAR-and AMPAR-mediated excitatory postsynaptic currents (EPSCs), overexpression of NL2 selectively increased inhibitory postsynaptic currents (IPSCs), and overexpression of NL4 paradoxically decreased NMDAR-and AMPAR-mediated EPSCs, whereas overexpression of NL3 produced no electrophysiological effect (Chubykin et al., 2007; Ko et al., 2009b; Zhang et al., 2009; Chanda et al., 2013). "
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    ABSTRACT: Neuroligins are postsynaptic cell-adhesion molecules that bind presynaptic neurexins and are genetically linked to autism. Neuroligins are proposed to organize synaptogenesis and/or synaptic transmission, but no systematic analysis of neuroligins in a defined circuit is available. Here, we show that conditional deletion of all neuroligins in cerebellar Purkinje cells caused loss of distal climbing-fiber synapses and weakened climbing-fiber but not parallel-fiber synapses, consistent with alternative use of neuroligins and cerebellins as neurexin ligands for the excitatory climbing-fiber versus parallel-fiber synapses. Moreover, deletion of neuroligins increased the size of inhibitory basket/stellate-cell synapses but simultaneously severely impaired their function. Multiple neuroligin isoforms differentially contributed to climbing-fiber and basket/stellate-cell synapse functions, such that inhibitory synapse-specific neuroligin-2 was unexpectedly essential for maintaining normal climbing-fiber synapse numbers. Using systematic analyses of all neuroligins in a defined neural circuit, our data thus show that neuroligins differentially contribute to various Purkinje-cell synapses in the cerebellum in vivo. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 08/2015; 87(4). DOI:10.1016/j.neuron.2015.07.020 · 15.05 Impact Factor
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    • "The shared cytoplasmic tail of neurexins interacts with presynaptic scaffolding proteins (Butz et al., 1998), whereas alternative splicing at the extracellular domain modulates the binding to postsynaptic partners, such that maximal binding to neuroligins is exhibited by neurexin-1b variants lacking an insertion at splice site 4 (-S4) (Boucard et al., 2005; Comoletti et al., 2006; Dean et al., 2003). Thus, to uncouple neurexin-1b function, we generated a hemagglutinin (HA)-tagged deletion mutant of neurexin- 1b (-S4) that lacks the cytoplasmic tail (Figure 1A). "
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    ABSTRACT: Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic βNrx1ΔC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the βNrx1ΔC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of βNrx1ΔC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes.
    Cell Reports 07/2014; 8(2). DOI:10.1016/j.celrep.2014.06.022 · 8.36 Impact Factor
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    • "Several studies have identified factors responsible for differential splicing between the nervous system and other tissues (Boutz et al., 2007; Calarco et al., 2009; Gehman et al., 2011; Jensen et al., 2000), but it is not known to what extent differential splicing occurs between different neuronal cell types. While a number of individual cases have been identified (for examples, see Boucard et al., 2005; Chih et al., 2006; Miura et al., 2013), it has remained difficult to study the factors that might control neuron-subtype specificity of alternative splicing. This difficulty is largely due to the technical challenge of accurately measuring splicing differences between cells of the same tissue exhibiting little spatial separation. "
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    ABSTRACT: Alternative splicing is important for the development and function of the nervous system, but little is known about the differences in alternative splicing between distinct types of neurons. Furthermore, the factors that control cell-type-specific splicing and the physiological roles of these alternative isoforms are unclear. By monitoring alternative splicing at single-cell resolution in Caenorhabditis elegans, we demonstrate that splicing patterns in different neurons are often distinct and highly regulated. We identify two conserved RNA-binding proteins, UNC-75/CELF and EXC-7/Hu/ELAV, which regulate overlapping networks of splicing events in GABAergic and cholinergic neurons. We use the UNC-75 exon network to discover regulators of synaptic transmission and to identify unique roles for isoforms of UNC-64/Syntaxin, a protein required for synaptic vesicle fusion. Our results indicate that combinatorial regulation of alternative splicing in distinct neurons provides a mechanism to specialize metazoan nervous systems.
    Molecular Cell 06/2014; DOI:10.1016/j.molcel.2014.05.004 · 14.02 Impact Factor
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