Resolving Spatiotemporally-Specific Multicellular Dynamics In Vivo During Olfactory Neurogenesis

解决嗅觉神经发生过程中体内时空特异性多细胞动力学

• 批准号: 10624245
• 负责人: Ankur Saxena
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-10-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10624245
• 关键词: Address; Algorithms; Behavior; Biological; Biological Models; Cell Communication; Cells; Complex; Congenital Abnormality; Cues; Data; Defect; Development; Disease; Endocrine; Feedback; Genes; Genetic; Genetic Programming; Heat-Shock Response; Human; Investigation; Ligands; Link; Location; Mediating; Modeling; Molecular; Mus; Nature; Neural Crest; Neural Crest Cell; Neurologic; Neuronal Differentiation; Neurons; Notch Signaling Pathway; Notch and Wnt Signaling Pathway; Olfactory Epithelium; Olfactory Pathways; Output; Pathway interactions; Pattern; Phenotype; Pituitary Gland; Play; Population; Process; Resolution; Retina; Role; Secondary to; Sensory; Signal Pathway; Signal Transduction; Specific qualifier value; Specificity; System; Techniques; Testing; Time; Tissues; Vertebrates; WNT Signaling Pathway; Work; Zebrafish; cell behavior; cell motility; cell type; experimental study; genetic manipulation; in vivo; intercellular communication; migration; neurogenesis; notch protein; novel; olfactory neurogenesis; olfactory sensory neurons; receptor; spatiotemporal; stem cell migration; stem cell population; stem cells; temporal measurement; timeline; tool; transcription factor

Project Summary While many neurological defects and disorders are known to result from developmental perturbations in specific cell types and/or are linked to well-studied signaling pathways, the system-level coordination of multiple cell populations and the spatiotemporal specificity of their signaling outputs during neurogenesis remains poorly understood. The long-term objective of this proposal is to take advantage of the accessible and rapidly developing zebrafish olfactory epithelium to quantitatively characterize cell-cell signaling pathways and multicellular behaviors that drive the assembly of complex neuronal populations in vertebrates. Proposed experiments will test the hypothesis that the Notch and Wnt signaling pathways provide spatially- and temporally- sensitive cues to guide stem cell migration into the olfactory epithelium and regulate sensory neurogenesis. Small subsets of cells will be manipulated and analyzed completely in vivo, at subcellular spatial resolution and with sub-minute temporal resolution, so as to determine the system-level coordination of stem cell migration, specification, and differentiation during both normal and disrupted signaling. First, new tools and techniques will be used to perturb Wnt signaling in vivo at specific times and locations during olfactory development and to algorithmically model and explain progenitor cells’ migratory behavior. Next, Notch signaling will be manipulated in vivo to quantitate its effects on olfactory system-wide neurogenesis, and target genes will be identified that are required for neuronal specification and/or differentiation. Finally, the transcription factor insm1a will be similarly investigated to determine its role in Notch signaling-mediated olfactory neurogenesis. The approaches in this proposal will directly analyze in vivo data to understand and predict multicellular behavior without reducing biological complexity and help uncover phenotypes that may advance our broad understanding of system-wide neuronal differentiation and assembly in vivo.

项目概要 虽然已知许多神经系统缺陷和疾病是由特定的发育障碍引起的 细胞类型和/或与经过充分研究的信号通路、多个细胞的系统级协调有关 群体及其神经发生过程中信号输出的时空特异性仍然很差 明白了。该提案的长期目标是利用可访问且快速的 开发斑马鱼嗅觉上皮以定量表征细胞间信号传导途径和 驱动脊椎动物中复杂神经元群体组装的多细胞行为。建议的 实验将检验 Notch 和 Wnt 信号通路提供空间和时间的假设 引导干细胞迁移到嗅觉上皮并调节感觉神经发生的敏感线索。 将在亚细胞空间分辨率和体内完全操作和分析小部分细胞 具有亚分钟时间分辨率，从而确定干细胞迁移的系统级协调， 正常和中断信号传导过程中的规范和分化。首先，新的工具和技术将 用于在嗅觉发育过程中的特定时间和位置扰乱体内 Wnt 信号传导，并 通过算法建模并解释祖细胞的迁移行为。接下来，Notch 信号将被操纵 体内定量其对嗅觉系统范围神经发生的影响，并且将鉴定目标基因 是神经元规范和/或分化所必需的。最后，转录因子insm1a将是 类似地研究以确定其在 Notch 信号介导的嗅觉神经发生中的作用。方法 在该提案中，将直接分析体内数据以理解和预测多细胞行为，而不减少 生物复杂性并有助于揭示表型，从而促进我们对全系统的广泛理解 体内神经元分化和组装。