Non-Canonical Roles for Cell-Adhesion Molecules in Presynaptic Assembly

项目总结 突触的正确形成对神经回路的功能是不可或缺的。突触发生的中断 在发育早期会导致神经发育障碍，如自闭症或智力残疾。 然而，尽管经过了几十年的研究，突触的形成、成熟和维持的确切方式仍然存在 难以捉摸。细胞黏附分子(CAM)参与了突触的发生，因为它们的胞外反式-... 突触相互作用能够诱导突触组装并赋予突触伙伴特异性。 然而，调节其突触发生功能的细胞内信号通路却知之甚少。 利用线虫，我们已经鉴定出一对凸轮，SYG-1和SYG-2，可能具有非- 突触组装中的典型作用，在没有跨突触结合的情况下发挥调节作用 突触前组装。我们已经发现，仅SYG-2的胞内结构域就足以诱导 突触前组装，而不是公认的CAM胞外域是 它们的功能。利用CRISPR转基因，我将确定这种蛋白质和它已知的结合伙伴 SYG-1需要一起或分开来组织突触前特化。然后我会变异候选人 在其胞内区内结合基序，以阐明下游所需的胞内通路 它们的功能。这些实验将提供对可能的功能和潜在的机制的洞察。 SYG-1/SYG-2人类同源基因KIRREL3，与自闭症有关。

PROJECT SUMMARY The proper formation of synapses is integral to the function of neural circuits. Disruptions in synaptogenesis during early development can lead to neurodevelopmental disorders, such as autism or intellectual disability. Yet despite decades of study, precisely how synapses form, mature, and are maintained has remained elusive. Cell-adhesion molecules (CAMs) have been implicated in synaptogenesis, as their extracellular trans- synaptic interactions are capable of inducing synapse assembly and conferring synaptic partner specificity. However, the intracellular signaling pathways that mediate their synaptogenic functions are less understood. Using the roundworm C. elegans, we have identified a pair of CAMs, SYG-1 and SYG-2, that may have non- canonical roles in synapse assembly, functioning in the absence of trans-synaptic binding to regulate presynaptic assembly. We have found that the intracellular domain of SYG-2 alone is sufficient for inducing presynaptic assembly, in contrast to the accepted idea that the extracellular domains of CAMs are required for their function. Using CRISPR transgenesis, I will determine whether this protein and its known binding partner SYG-1 are required together or separately to organize presynaptic specializations. I will then mutate candidate binding motifs within their intracellular domains to elucidate the downstream intracellular pathways required for their function. These experiments will provide insight into the possible function and underlying mechanisms of SYG-1/SYG-2 human ortholog KIRREL3, which has been implicated in autism.