Uncovering the role of leukocyte cell-derived chemotaxin 2 (lect-2) in dendrite morphogenesis

项目摘要 长期以来，树突状细胞的异常形态与神经发育和 神经精神障碍，包括自闭症谱系障碍和精神分裂症。尽管 这些疾病中的许多表现为树突发育的特征性变化，缺乏完整的 了解调控树枝晶形成的基因和机制。在…上扩展 了解树枝晶发育的遗传和分子基础，这个项目将 使用线虫PVD神经元，其中的发育机制已知为 要节约。PVD神经元是多树突状神经元，形成特征性的烛台样神经元。 乔木，是多通道伤害性感受器。我们实验室和其他实验室的研究表明， 某些保守的细胞外黏附分子，包括mnr-1/menorin，SAX-7/L1CAM， 和dma-1/lrr跨膜受体，在调节PVD的树突状细胞发生中发挥作用。 神经元。然而，最近的发现表明，可能有更多的基因与PVD有关 发展。该项目旨在表征表型、遗传和分子功能。 发现线虫PVD神经元发育缺陷的一种新的保守基因。 为了解决新的信号分子与mnr-1，SAX-7， 和dma-1调节PVD树突分支的实验，解决了遗传，分子， 分子的表型作用也将发挥作用。双突变等实验 分析、免疫共沉淀和CRISPR/Cas9基因组编辑将被执行以测试 与mnr-1、sax-7和dma-1的遗传和物理相互作用。RNAi介导的击倒 候选受体基因的实验，以及与突变菌株的遗传杂交，将是 识别一个假定的受体，并拼凑出一个作用机制。一起， 这些实验将阐明一种新的保守信号分子在树突中的作用。 形态发生，有助于建立对基因调控的更完整的理解 发育过程中的神经生长和潜在的新诊断。

Project Summary Aberrant dendrite morphologies have long been associated with neurodevelopmental and neuropsychiatric disorders, including Autism Spectrum Disorders and schizophrenia. Though many of these disorders show characteristic changes in dendrite development, there lacks a full understanding of the genes and mechanisms that regulate dendrite formation. To expand upon the knowledge of the genetic and molecular basis of dendrite development, this project will employ the use of C. elegans PVD neurons, in which mechanisms of development are known to be conserved. PVD neurons are multi-dendritic neurons that form characteristic candelabra-like arbors, and are polymodal nociceptors. Studies from our lab, and others, have shown that certain conserved extracellular adhesion molecules, including mnr-1/Menorin, sax-7/L1CAM, and dma-1/LRR transmembrane receptor, play a role in regulating dendritogenesis of PVD neurons. However, recent findings suggest that there may be more genes involved in PVD development. This project aims to characterize the phenotypic, genetic, and molecular functions of a novel conserved gene that reveals developmental defects in the C. elegans PVD neurons. To address the hypothesis that the novel signaling molecule works in concert with mnr-1, sax-7, and dma-1 to regulate PVD dendrite branching, experiments addressing the genetic, molecular, and phenotypic roles of the molecule will be performed. Experiments such as double mutant analyses, co-immunoprecipitation, and CRISPR/Cas9 genome editing will be executed to test genetic and physical interactions with mnr-1, sax-7, and dma-1. RNAi mediated knock-down experiments of candidate receptor genes, along with genetic crosses with mutant strains, will be performed to identity a putative receptor and piece together a mechanism of action. Together, these experiments will elucidate the role of a novel conserved signaling molecule in dendrite morphogenesis, helping to create a more complete understanding of the genes regulating neural growth during development and harboring potential for novel diagnoses.