Understanding the regulation of neuron cell number and arbor size

了解神经元细胞数量和乔木大小的调节

• 批准号: 10327719
• 负责人: Jennifer A Malin
• 金额: $ 14.03万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10327719
• 关键词: Address; Adult; Apoptosis; Bioinformatics; Biological; Biology; Birth; Blindness; Brain; Brain Injuries; Brain region; Candidate Disease Gene; Cell Count; Cell Death; Cell Death Inhibition; Cell fusion; Cells; Complex; Comprehension; Data; Data Set; Development; Drosophila genus; Ensure; Environment; Exhibits; Eye; Failure; Ganglia; Generations; Genetic; Genetic Processes; Genetic Transcription; Goals; Image; Imaging Techniques; Inhibition of Apoptosis; Kinetics; Learning; Libraries; Location; Logic; Maps; Medical center; Memory; Mentorship; Modeling; Molecular; Molecular Target; Morphology; Mosaicism; Mutate; Nerve Degeneration; Neurobiology; Neuroepithelial; Neurology; Neurons; Neuropeptides; Neuropil; New York; Optic Lobe; Optics; Pattern; Phase; Photoreceptors; Population; Regenerative Medicine; Regulation; Retina; Role; Sampling; Specific qualifier value; Structure; System; Testing; Time; To specify; Transcript; Transplantation; Universities; Visual; Visual system structure; Work; cell type; developmental neurobiology; experimental study; fly; genetic manipulation; machine learning algorithm; nerve stem cell; nervous system disorder; neuroblast; neuroepithelium; novel; overexpression; prevent; progenitor; receptor; relating to nervous system; retinotopic; single-cell RNA sequencing; somatosensory; stem cell division; stem cell therapy; transcription factor; transcriptome; transcriptome sequencing; two-photon

PROJECT SUMMARY/ABSTRACT How the brain generates the correct number of neurons and how these neurons determine the size of their arbors to innervate the receptor field is a critical question in neurobiology. The Drosophila visual system is hard wired and iteratively organized into columns, providing an excellent model to answer these questions. Drosophila medulla multicolumnar neurons exhibit 5 to 750 neurons per cell type; each neuron class possesses a distinct morphology and projects its arbors across multiple columns in the optic lobe. The host lab has obtained single-cell RNA sequencing (scRNAseq) data that determined the transcriptome of almost all optic lobe neuron cell types throughout development. The first aim of this project is to understand the molecular and cell biological mechanisms that dictate neuron number. Under the mentorship of Claude Desplan at New York University (K99 phase), I will perform genetics experiments that decisively address the role of programmed cell death, neural stem cell division number, and neuroepithelial size of origin in regulating the number of multicolumnar neurons produced. I will also perform lineage tracing experiments to determine whether molecularly similar cell types are generated at the same time. With Holger Knaut at NYU Medical Center, I will learn quantitative live imaging techniques to distinguish whether neural stem cells divide a limited number of times to generate low-abundance neural classes, or whether cell fusion of immature progenitors drives cell number. The second aim of this project is to determine the morphological and genetic processes that dictate the size and orientation of the arbors of multicolumnar to allow them to cover distinct receptor fields. With the bioinformatics expertise of Itai Yanai at NYU Medical Center, I will perform RNAseq on adult neurons that are not numerous enough to be identified in our existing scRNAseq data sets. I will then use machine learning algorithms to identify these neurons during development in our existing scRNAseq libraries and thus identify candidate genes required for the regulation of neuron number and arbor size (R00 phase). I will combine these molecular experiments with live imaging to quantitatively characterize how multicolumnar neurons determine the orientation and size of their arbors. Preliminary data indicates that cell death and the size of neuroepithelial region of origin in part dictate multicolumnar neuron number; I have also identified a neuropeptide whose function is essential for the regulation of neuron arbor size. My work will clarify the molecular basis of neuron abundance and determine how neurons present in small numbers regulate their arbor size to ensure that their environment is uniformly sampled, a problem common to many brain regions in most species.

项目总结/摘要 大脑如何产生正确数量的神经元，以及这些神经元如何决定它们的大小。 神经支配受体场的神经元是神经生物学中的一个关键问题。果蝇的视觉系统 连接并迭代地组织成列，提供了一个回答这些问题的极好模型。 果蝇延髓多柱神经元表现出5至750神经元每细胞类型;每类神经元 具有独特的形态，并将其乔木投射在视叶的多个柱上。主机实验室 已经获得了单细胞RNA测序（scRNAseq）数据，确定了几乎所有的转录组， 视叶神经元细胞类型。 这个项目的第一个目标是了解决定神经元的分子和细胞生物学机制 number.在纽约大学（K99阶段）的克劳德·德斯普兰的指导下，我将进行遗传学研究。 决定性地解决程序性细胞死亡，神经干细胞分裂数量， 神经上皮大小的起源在调节产生的多柱神经元的数量。我也会表演 谱系追踪实验，以确定分子相似的细胞类型是否在同一时间产生， 时间我将与纽约大学医学中心的Holger Knaut一起学习定量活体成像技术， 神经干细胞是否分裂有限次数以产生低丰度神经类，或 未成熟祖细胞的细胞融合是否驱动细胞数量。 这个项目的第二个目的是确定决定大小的形态和遗传过程 和方向的多柱的乔木，使他们能够覆盖不同的受体领域。与 利用纽约大学医学中心的Itai柳井的生物信息学专业知识，我将对成年神经元进行RNAseq， 数量不足以在我们现有的scRNAseq数据集中识别。然后我将使用机器学习 算法可以在我们现有的scRNAseq库中开发期间识别这些神经元，从而识别 神经元数量和乔木大小调节所需的候选基因（R 00期）。我会把这些联合收割机 用活体成像进行分子实验，以定量表征多柱神经元如何确定 树木的方向和大小初步数据表明，细胞死亡和神经上皮细胞的大小 起源区域部分决定了多列神经元的数量;我还鉴定了一种神经肽， 功能对于调节神经元乔木大小是必不可少的。我的工作将阐明神经元的分子基础 并确定少量存在的神经元如何调节它们的乔木大小，以确保它们的 环境是均匀采样的，这是大多数物种的许多大脑区域都存在的问题。