Article

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.

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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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    • "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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