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.

项目摘要/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确定其大小 支配受体场的乔木是神经生物学中的关键问题。果蝇视觉系统很难 连线和迭代组织成柱，提供了一个出色的模型来回答这些问题。 果蝇髓质多腹神经元每种细胞的神经元5至750个神经元；每个神经元类 具有独特的形态，并在视位叶中的多个柱上投射了轴承。主机实验室 已经获得了单细胞RNA测序（SCRNASEQ）数据，该数据几乎确定了几乎所有的转录组 整个发育过程中，视位叶神经元细胞类型。 该项目的第一个目的是了解决定神经元的分子和细胞生物学机制 数字。在纽约大学（K99阶段）的Claude Desplan的指导下，我将执行遗传学 果断地解决了程序性细胞死亡，神经干细胞分裂的作用和 在调节产生的多斑点神经元数量时，神经上皮大小。我也会表演 谱系跟踪实验，以确定是否在相同的情况下生成分子相似的细胞类型 时间。在纽约大学医疗中心的Holger Knaut的情况下，我将学习定量实时成像技术以区分 神经干细胞是划分有限的次数以产生低丰度的神经类别还是 未成熟祖细胞的细胞融合是否驱动细胞数。 该项目的第二个目的是确定决定规模的形态和遗传过程 以及多肢体的乔木的方向，以允许它们覆盖不同的受体场。与 纽约大学医学中心的ITAI Yanai的生物信息学专业知识，我将对成人神经元进行RNASEQ 在我们现有的SCRNASEQ数据集中识别的数量不足。然后我将使用机器学习 在我们现有的Scrnaseq库中开发过程中识别这些神经元的算法，从而确定 神经元数和乔木大小（R00期）所需的候选基因。我将结合这些 具有实时成像的分子实验，以定量表征多斑点神经元如何确定 他们的方向盘的方向和大小。初步数据表明细胞死亡和神经上皮的大小 原籍地区部分决定了多壁神经元数；我还确定了一种神经肽 功能对于调节神经乔植物大小至关重要。我的工作将阐明神经元的分子基础 丰度并确定少量神经元如何调节其乔木大小，以确保其 环境均匀地采样，大多数物种中许多大脑区域常见的问题。