Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons (original) (raw)

formation in the central nervous system (CNS) are not known. While agrin is found at central synapses, mice lacking agrin do not show any defects in CNS synaptogenesis (Serpinskaya et al., 1999). Other proteins that have been suggested to mediate CNS synaptogenesis Summary the spider venom ␣-latrotoxin, which triggers massive neurotransmitter release . Unfor-Most neurons form synapses exclusively with other tunately, it has so far not been possible to localize neuneurons, but little is known about the molecular mechrexins in the mammalian CNS at the ultrastructural level, anisms mediating synaptogenesis in the central nerand their synaptic localization therefore remains to be vous system. Using an in vitro system, we demonstrate demonstrated. Thousands of neurexin variants are genthat neuroligin-1 and -2, postsynaptically localized erated through alternative splicing, and this molecular proteins, can trigger the de novo formation of presyndiversity has been hypothesized to generate specificity aptic structure. Nonneuronal cells engineered to exduring synaptogenesis (Missler et al., 1998). More repress neuroligins induce morphological and functional cently, other proteins with sequence similarity to neupresynaptic differentiation in contacting axons. This rexin-1, -2, and -3 have been identified and were shown activity can be inhibited by addition of a soluble version to mediate interactions between axons and glia cells of ␤-neurexin, a receptor for neuroligin. Furthermore, (reviewed in Bellen et al., 1998). Since these proteins addition of soluble ␤-neurexin to a coculture of defined only partially share the domain structure of neurexin-1, pre-and postsynaptic CNS neurons inhibits synaptic -2, and -3, it is unclear whether they are bona fide neuvesicle clustering in axons contacting target neurons. rexins (Missler et al., 1998). Our results suggest that neuroligins are part of the While the presynaptic localization of neurexins remachinery employed during the formation and remodmains to be demonstrated, neuroligin-1, a ligand of a eling of CNS synapses. specific splice variant of ␤-neurexins, has been clearly shown to localize to the postsynaptic compartment at Introduction excitatory synapses (Song et al., 1999). So far, three neuroligin genes have been described in the rat, and The excitable cells of the nervous system are joined into the predicted products of these genes are 52% identical a network by connections called synapses (Sherrington, at the amino acid level (Ichtchenko et al., 1995, 1996). 1906). This synaptic network develops as axons extend Structurally, neuroligins possess in their cytoplasmic from presynaptic neurons and grow to reach their cordomain a PDZ binding motif that mediates interactions rect postsynaptic partners. Extending axons are guided with synaptic scaffolding proteins such as PSD-95 (Irie along specific trajectories and by cues present in their et al., 1997). The extracellular domain of neuroligins conimmediate environment (Sanes and Yamagata, 1999).