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: 10377439
• 负责人: Ankur Saxena
• 金额: $ 31.99万
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10377439
• 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; Lead; Ligands; Link; Location; Mediating; Modeling; Molecular; Mus; Names; 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; Specificity; System; Techniques; Testing; Time; TimeLine; Tissues; Vertebrates; WNT Signaling Pathway; Work; Zebrafish; base; 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; 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.

项目摘要 尽管许多神经系统缺陷和疾病是由于特定的发育扰动而造成的 细胞类型和/或与研究充分的信号通路相关，该系统级配位多个单元格 神经发生过程中其信号传导输出的人群及其时空特异性仍然很差 理解齿。该提议的长期目标是利用可访问和迅速的优势 开发斑马鱼嗅觉上皮，以定量地表征细胞细胞信号通路和 驱动脊椎动物中复杂神经元种群组装的多细胞行为。建议的 实验将检验以下假设：凹槽和Wnt信号通路在空间和临时提供的假设 敏感的提示引导干细胞迁移到嗅觉上皮并调节感觉神经发生。 小细胞子集将在体内，亚细胞空间分辨率和 通过亚分钟临时分辨率，以确定干细胞迁移的系统级配位 规格和正常和中断信号传导期间的分化。首先，新工具和技术将 在特定时间和嗅觉发育期间的特定时间和位置来扰动Wnt信号传导 算法对祖细胞的迁移行为进行建模并解释。接下来，将操纵Notch信号 在体内量化其对嗅觉全系统神经发生的影响，将确定靶基因 是神经元规范和/或分化所必需的。最后，转录因子insm1a将是 类似地研究了其在Notch信号介导的嗅觉神经发生中的作用。方法 在此提案中，将直接分析体内数据，以理解和预测多细胞行为而无需降低。 生物学复杂性并帮助发现可能提高我们对系统范围内广泛理解的表型 神经元分化和体内组装。