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

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

展开

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.

项目摘要突触的正确形成与神经回路的功能不可或缺。突触发生的破坏在早期发展过程中，会导致神经发育障碍，例如自闭症或智力障碍。然而，尽管研究了数十年，但仍然存在突触的形成，成熟和维持的方式仍然存在难以捉摸。细胞粘附分子（CAM）已与突触发生有关突触相互作用能够诱导突触组装并赋予突触伴侣特异性。但是，介导其突触功能的细胞内信号通路知之甚少。使用round虫秀丽隐杆线虫，我们已经确定了一对cam，SYG-1和SYG-2，可能具有非 - 在突触组件中的规范作用，在没有反式突触结合的情况下起作用以调节突触前组装。我们发现，仅SYG-2的细胞内结构域就足以诱导与公认的观念相比，突触前组装需要凸轮的细胞外域他们的功能。使用CRISPR转基因，我将确定该蛋白质及其已知结合伴侣是否 SYG-1需要共同或分别组织突触前专业。然后我会变异候选人其细胞内结构域内的结合基序，以阐明他们的功能。这些实验将洞悉可能的功能和潜在机制 Syg-1/syg-2人类直系同源物kirrel3，与自闭症有关。