Tissue flow genetics: using cartography to reveal forces driving morphogenesis

摘要 器官在发育过程中获得的形式对其功能至关重要。例如， 心脏发育过程中的循环导致先天性心脏病--这是观察到的最常见的出生缺陷 在人类身上。虽然许多研究已经确定了细胞是如何注定要执行它们的任务的，但我们对它们的作用知之甚少。 塑造组织的力量转录因子（TF）跨越多个长度尺度-从几个 到数百个细胞-精确地调节基因表达程序。这些程序产生了 引起细胞行为的压力。为了确保器官具有对其功能至关重要的正确形状， 物理应力必须在跨越多个长度尺度的组织上协调。我们开始 了解短程TF如何在单个细胞水平上控制物理应力。该提案寻求 为了揭示组织是如何被物理应力塑造的，在器官尺度上控制，使用D。melanogaster 作为一个模型系统。 用于全活成像和组织制图的新方法已经揭示：细胞行为沿着 背腹（DV）轴在生殖带延伸。DV行为调节在背化突变体中丢失。 这些发现挑战了这样的假设，即长距离TF，如Dorsal，仅通过建立间接作用。 短距离模式来控制压力为了验证长距离TF调节物理应力的假设， 负责器官的形状，我们提出：目的1，测量物理应力在器官的规模，并通过 与已知TF表达模式进行系统比较，确定Dorsal在器官规模应激中的作用 协同在aim 2中，我们将扩展我们的观察，以研究细胞行为的协调， 异源组织层在中肠循环。 该研究将定量实验与理论相结合，为 测量TF介导的塑造器官的整体应力协调。最先进的显微镜和工具 用于分析产生复杂形状的细胞行为的设计将为 了解复杂的器官是如何形成的，包括循环

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.