Tissue flow genetics: using cartography to reveal forces driving morphogenesis

组织流遗传学：利用制图揭示驱动形态发生的力量

• 批准号: 9316689
• 负责人: Sebastian J Streichan
• 金额: $ 14.34万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316689
• 关键词: Actomyosin; Animals; Apoptosis; Atlases; Behavior; Biological Models; Biology; Cell Cycle; Cells; Collecting Tube; Complex; Congenital Abnormality; Cytoskeleton; Data; Development; Developmental Biology; Dorsal; Drosophila genus; Embryo; Ensure; Foundations; Gene Expression; Gene Expression Profile; Genetic; Growth; Human; Image; Individual; Lateral; Length; Light; Link; Measures; Mechanical Stress; Mechanics; Mediating; Methods; Microscope; Midgut; Midgut Loop; Modeling; Morphogenesis; Motor; Movement; Myosin ATPase; NF-kappa B; New Territories; Organ; Pattern; Phase; Physics; Positioning Attribute; Postdoctoral Fellow; Research; Resolution; Rest; Role; Scientific Inquiry; Shapes; Side; Signal Transduction; Stress; Stretching; Structure; System; Testing; Time; Tissue Engineering; Tissues; Transcriptional Regulation; Tube; cardiogenesis; cell behavior; cell motility; cell type; congenital heart disorder; design; driving force; experimental study; imprint; insight; intercalation; member; morphogens; mutant; novel; programs; theories; tool; transcription factor

ABSTRACT  The form that organs acquire during development is critical for their functionality. For example, failed tissue  looping during heart development results in congenital heart disease -­ the most common birth defect observed  in humans. While many studies have identified how cells are fated to perform their tasks, we know little about the forces that shape tissues. Transcription factors (TFs) spanning multiple length scales - ranging from a few to hundreds of cells - precisely regulate gene expression programs. These programs generate the physical stresses that give rise to cell behavior. To ensure that organs take on their proper shape vital for their function, physical stresses must be coordinated across tissues spanning multiple length scales. We are beginning to understand how short-ranged TFs control physical stresses at the level of individual cells. This proposal seeks to uncover how tissues are shaped by physical stresses, controlled at the organ scale, using D. melanogaster as a model system. Novel methods for in toto live imaging and tissue cartography have revealed: cell behavior is modulated along the dorsoventral (DV) axis during germband extension. DV behavior modulation is lost in dorsalizing mutants. These findings challenge the assumption, that long-range TFs, such as Dorsal, act only indirectly by setting up short-range patterns to control stress. To test the hypothesis that long-range TFs modulate physical stresses responsible for organ shape, we propose: Aim 1 to measure physical stress at the organ scale, and by systematic comparison to known TF expression patterns, identify the role of Dorsal in organ scale stress coordination. In aim 2 we will extend our observations to investigate coordination of cell behavior across heterologous tissue layers during midgut looping. The proposed research combines quantitative experiments with theory, to provide the first strategy for measuring TF mediated global stress coordination that shapes organs. State of the art microscopes and tools designed for analyzing cell behaviors that produce complex shapes will open new opportunities for understanding how intricate organs form, including loops.

抽象的 器官在开发过程中获得的形式对于它们的功能至关重要。例如，组织失败 心脏发育期间循环导致先天性心脏病 - 最常见的生日缺陷 在人类中。尽管许多研究已经确定了细胞如何执行其任务，但我们对 塑造组织的力。跨越多个长度尺度的转录因子（TF） - 从几个 到数百个细胞 - 精确调节基因表达程序。这些程序生成物理 引起细胞行为的压力。为了确保器官对其功能至关重要的适当形状， 身体应力必须在跨越多个长度尺度的组织中协调。我们开始 了解短距离TFS如何控制单个细胞水平的身体应力。该建议寻求 使用D. melanogaster揭示如何通过身体应力来控制组织的形状，并在器官尺度上控制 作为模型系统。 Toto实时成像和组织制图中的新方法已经揭示了：细胞行为沿 胚芽延伸过程中的背腹轴（DV）轴。 DV行为调制在背层突变体中丢失。 这些发现挑战了以下假设，即远程TF（例如背侧）仅通过设置而间接起作用 短距离模式以控制应力。测试远距离TFS调节物理应力的假设 负责器官形状，我们建议：目标1在器官尺度上测量身体压力，并通过 与已知TF表达模式的系统比较，确定背侧在器官尺度应力中的作用 协调。在AIM 2中，我们将扩展观察结果，以调查整个细胞行为的协调 中肠循环期间异源组织层。 拟议的研究将定量实验与理论相结合，以提供第一个策略 测量塑造器官的TF介导的全球应力协调。最先进的显微镜和工具 专为分析产生复杂形状的细胞行为而设计的将为新的机会开放 了解包括循环在内的复杂器官的形式。