Neurexin mediates the assembly of presynaptic terminals

Abstract

Neurexins are a large family of proteins that act as neuronal cell-surface receptors. The function and localization of the various neurexins, however, have not yet been clarified. Beta-neurexins are candidate receptors for neuroligin-1, a postsynaptic membrane protein that can trigger synapse formation at axon contacts. Here we report that neurexins are concentrated at synapses and that purified neuroligin is sufficient to cluster neurexin and to induce presynaptic differentiation. Oligomerization of neuroligin is required for its function, and we find that beta-neurexin clustering is sufficient to trigger the recruitment of synaptic vesicles through interactions that require the cytoplasmic domain of neurexin. We propose a two-step model in which postsynaptic neuroligin multimers initially cluster axonal neurexins. In response to this clustering, neurexins nucleate the assembly of a cytoplasmic scaffold to which the exocytotic apparatus is recruited.

Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice

“…The synaptic proteins neurexins (Nrxns) and neuroligins (Nlgns) have emerged as a pair of fascinating candidates for underlying synaptic plasticity. Presynaptic Nrxns form transsynaptic complexes with postsynaptic Nlgns (Ushkaryov et al 1992;Yamagata et al 2003) and play an important role in differentiation, maturation, and stabilization of both excitatory and inhibitory synapses (Dean et al 2003;Graf et al 2004;Chubykin et al 2007;Budreck and Scheiffele 2007;Krueger et al 2012). These proteins not only facilitate the assembly of functional units on their own side of the synapses but also regulate synaptic specialization on the opposite side of a nascent synapse through their trans-synaptic interactions (Dean and Dresbach 2006).…”

Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis

“…Swapping the extracellular cholinesterase (ChoE)-like domain of NL1 with the homologous cholinesterase sequence creates a chimera, NL1-SWAP, that is expressed and trafficked correctly, but cannot interact with presynaptic Nrxs 23 (Extended Data Fig. 4i).…”

“…Full length NL1 (HA-NL1) is effectively silenced by the shrtNL1, whereas NL1 shRNA-resistant mutant (HA-NL1-RM) and NL1-SWAP are not silenced by shrtNL1. Note: NL1-SWAP runs smaller than full-length NL1 (previously published in 23 ). c , Western blot analyses of cell lysates from HEK293 cells transfected with shCtrl or shNL2 with HA-tagged NL2 or HA-tagged NL2-RM.…”

“…In a previous study, a chimera of NL1 (NL1-SWAP) was created in which the ChoE-like domain is swapped for the ChoE sequence. This chimera is efficiently trafficked to the cell surface, but fails to interact transcellularly with Nrx-βs 23 . j , Representative images of astrocytes over-expressing EGFP (green) and HA-tagged NLs (red) in co-culture with neurons (not visible).…”

Characterization of the neuroligin gene family expression and evolution in zebrafish

“…Although different works suggested their involvement in synapses formation (Scheiffele et al, 2000;Dean et al, 2003;Graf et al, 2004;Prange et al, 2004;Chubykin et al, 2005;Levinson et al, 2005), other studies and the analysis of knockout mice proposed that Neuroligins, along with the alphaforms of Neurexins, are involved in synaptic function and maturation (Missler et al, 2003;Sara et al, 2005;Varoqueaux et al, 2006;Chubykin et al, 2007). Triple knockout mice lacking Nlgn1-3 die shortly after birth and present normal synapse numbers with an apparently normal ultrastructure (Varoqueaux et al, 2006).…”