Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19432-7. doi: 10.1073/pnas.1217633109. Epub 2012 Nov 5.
The transsynaptic complex of neuroligin (NLGN) and neurexin forms a physical connection between pre- and postsynaptic neurons that occurs early in the course of new synapse assembly. Both neuroligin and neurexin have, indeed, been proposed to exhibit active, instructive roles in the formation of synapses. However, the process by which these instructive roles play out during synaptogenesis is not well understood. Here, we examine one aspect of postsynaptic neuroligin with regard to its synaptogenic properties: its basal state as a constitutive dimer. We show that dimerization is required for the synaptogenic properties of neuroligin and likely serves to induce presynaptic differentiation via a transsynaptic clustering of neurexin. Further, we introduce chemically inducible, exogenous dimerization domains to the neuroligin molecule, effectively bestowing chemical control of neuroligin dimerization. This allows us to identify the acute requirements of neuroligin dimerization by chemically manipulating the monomeric-to-dimeric conversion of neuroligin. Based on the results of the inducible dimerization experiments, we propose a model in which dimerized neuroligin induces the mechanical clustering of presynaptic molecules as part of a requisite step in the coordinated assembly of a chemical synapse.
神经突黏附蛋白（NLGN）和神经连接蛋白（neurexin）的跨突触复合物在新突触形成的早期阶段，在突触前和突触后神经元之间形成物理连接。神经突黏附蛋白和神经连接蛋白都被认为在突触形成过程中具有主动的、指导作用。然而，这些指导作用在突触发生过程中的作用方式还不是很清楚。在这里，我们研究了神经突黏附蛋白的一个突触发生特性方面的问题：它作为一个组成型二聚体的基础状态。我们表明，二聚化对于神经突黏附蛋白的突触发生特性是必需的，并且可能通过神经连接蛋白的跨突触聚类来诱导突触前分化。此外，我们将化学诱导的、外源性二聚化结构域引入神经突黏附蛋白分子中，有效地赋予了神经突黏附蛋白二聚化的化学控制。这使我们能够通过化学操纵神经突黏附蛋白的单体到二聚体的转化，来确定神经突黏附蛋白二聚化的急性需求。基于诱导二聚化实验的结果，我们提出了一个模型，其中二聚化的神经突黏附蛋白诱导突触前分子的机械聚类，作为协调组装化学突触的必需步骤的一部分。
