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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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育过程中可能会导致神经发育障碍，例如自闭症或智力障碍。然而，尽管经过数十年的研究，突触的形成、成熟和维持的确切方式仍然没有得到解决。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，人们对介导其突触功能的细胞内信号传导途径知之甚少。使用线虫线虫，我们鉴定了一对 CAM，SYG-1 和 SYG-2，它们可能具有非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组装。我们发现仅 SYG-2 的胞内结构域就足以诱导突触前组装，这与 CAM 的胞外域是突触前组装所必需的公认观点相反他们的功能。使用 CRISPR 转基因技术，我将确定该蛋白质及其已知的结合伙伴是否 SYG-1 需要一起或单独来组织突触前专门化。然后我将变异候选人其胞内结构域内的结合基序以阐明下游胞内途径他们的功能。这些实验将深入了解其可能的功能和潜在机制 SYG-1/SYG-2 人类直系同源基因 KIRREL3，与自闭症有关。