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

细胞粘附分子在突触前组装中的非典型作用

• 批准号: 10751904
• 负责人: Jada Summerville
• 金额: $ 4.77万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-15 至 2026-12-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751904
• 关键词: Affect; Amino Acids; Auxins; Axon; Binding; Biological Models; Biological Process; Brain; CRISPR/Cas technology; Caenorhabditis elegans; Cell Adhesion Molecules; Cells; Cholinergic Receptors; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Defect; Development; Disease; Dorsal; Evolution; Extracellular Domain; Gene Transfer Techniques; Genetic; Hermaphroditism; Homologous Gene; Human; Impairment; Individual; Intellectual functioning disability; Knock-out; Lead; Length; Location; Maintenance; Maps; Mediating; Modeling; Motor Neurons; Mutate; Mutation; Nematoda; Nervous System; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Orthologous Gene; Pathway interactions; Process; Proteins; Quality of life; Role; Signal Pathway; Specific qualifier value; Specificity; Study models; Synapses; System; Tertiary Protein Structure; Testing; Time; Work; autism spectrum disorder; connectome; experimental study; extracellular; insight; mutant; negative affect; neural; neural circuit; neurodevelopment; overexpression; postsynaptic; presynaptic; synaptogenesis

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.

项目摘要 突触的正确形成是神经回路功能不可或缺的一部分。突触发生中断 在早期发展过程中可能导致神经发育障碍，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是未知的。 难以捉摸。细胞粘附分子（CAM）与突触发生有关，因为它们的细胞外跨膜转运， 突触相互作用能够诱导突触组装并赋予突触配偶体特异性。 然而，介导其突触发生功能的细胞内信号传导途径却知之甚少。 利用蛔虫C.我们已经确定了一对CAM，SYG-1和SYG-2，可能有非- 在突触组装中的典型作用，在缺乏跨突触结合的情况下发挥作用，以调节 突触前装配我们已经发现单独SYG-2的胞内结构域足以诱导 突触前组装，与公认的观点相反，CAM的胞外结构域是突触前组装所必需的。 它们的功能。利用CRISPR转基因技术，我将确定这种蛋白质及其已知的结合伴侣 SYG-1需要一起或单独组织突触前特化。然后我会让候选人 结合基序在其细胞内结构域，以阐明下游细胞内途径所需的 它们的功能。这些实验将提供对可能的功能和潜在机制的洞察， SYG-1/SYG-2人类直系同源物KIRK 3，其与自闭症有关。