The formation of mammalian synapses entails the precise alignment of presynaptic release sites with postsynaptic receptors but how nascent cell–cell contacts translate into assembly of presynaptic specializations remains unclear. Guided by pioneering work in invertebrates, we hypothesized that in mammalian synapses, liprin-α proteins directly link trans-synaptic initial contacts to downstream steps. Here we show that, in human neurons lacking all four liprin-α isoforms, nascent synaptic contacts are formed but recruitment of active zone components and accumulation of synaptic vesicles is blocked, resulting in ‘empty’ boutons and loss of synaptic transmission. Interactions with presynaptic cell adhesion molecules of either the LAR-RPTP family or neurexins via CASK are required to localize liprin-α to nascent synaptic sites. Liprin-α subsequently recruits presynaptic components via a direct interaction with ELKS proteins. Thus, assembly of human presynaptic terminals is governed by a hierarchical sequence of events in which the recruitment of liprin-α proteins by presynaptic cell adhesion molecules is a critical initial step.

哺乳动物突触的形成需要突触前释放位点与突触后受体的精确对准，但新生细胞与细胞的接触如何转化为突触前特化的组装仍不清楚。在无脊椎动物的开创性工作的指导下，我们假设在哺乳动物突触中，脂蛋白-α 蛋白直接将跨突触初始接触与下游步骤连接起来。在这里，我们表明，在缺乏所有四种 liprin-α 同种型的人类神经元中，形成了新生突触接触，但活性区成分的募集和突触小泡的积累被阻止，导致“空”布顿和突触传递的损失。将 liprin-α 定位到新生突触位点需要通过 CASK 与 LAR-RPTP 家族的突触前细胞粘附分子或神经毒素相互作用。Liprin-α 随后通过与 ELKS 蛋白的直接相互作用来招募突触前成分。因此，人类突触前末梢的组装是由一系列事件序列控制的，其中突触前细胞粘附分子招募脂蛋白-α 蛋白是关键的初始步骤。