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: 15.98). 11/2005; 48(2):229-36. DOI: 10.1016/j.neuron.2005.08.026
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Antony A Boucard, Jul 08, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 14.46 Impact Factor
  • Source
    • "Cerebellar Sam68 KO neurons fail to increase exon skipping at the Nrxn1 alternatively spliced segment 4 (AS4) upon neuronal depolarization. In wild-type neurons, this SAM68- dependent exon skipping results in production of NRX protein variants with altered ligand interactions (Boucard et al., 2005; Chih et al., 2006; Graf et al., 2006; Uemura et al., 2010; Iijima et al., 2011; Matsuda and Yuzaki, 2011; Aoto et al., 2013). Consistent with an important function for SAM68 in vivo, there is a corresponding reduction in the skipped AS4() transcript in Sam68 KO brains. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The unique functional properties and molecular identity of neuronal cell populations rely on cell type-specific gene expression programs. Alternative splicing represents a powerful mechanism for expanding the capacity of genomes to generate molecular diversity. Neuronal cells exhibit particularly extensive alternative splicing regulation. We report a highly selective expression of the KH domain-containing splicing regulators SLM1 and SLM2 in the mouse brain. Conditional ablation of SLM1 resulted in a severe defect in the neuronal isoform content of the polymorphic synaptic receptors neurexin-1, -2, and -3. Thus, cell type-specific expression of SLM1 provides a mechanism for shaping the molecular repertoires of synaptic adhesion molecules in neuronal populations in vivo.
    The Journal of Cell Biology 01/2014; DOI:10.1083/jcb.201310136 · 9.69 Impact Factor