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它们的功能至关重要。例如，失败的器官组织。 在心脏发育过程中循环死亡会导致先天性心脏病，这是目前观察到的最常见的出生缺陷。 在人类中。虽然许多研究已经确定了细胞是如何注定要执行任务的，但我们对此知之甚少 塑造组织的力量。跨越多个长度尺度的转录因子(TF)-从几个 到数百个细胞--精确地调控基因表达程序。这些程序产生了物理上的 导致细胞行为的压力。为了确保器官呈现出对其功能至关重要的适当形状， 物理应力必须在跨越多个长度尺度的组织中协调。我们开始 了解短程TF是如何在单个细胞水平上控制物理压力的。这项提议旨在 为了揭示组织是如何通过物理压力形成的，并在器官尺度上进行控制，使用D. 作为一个模范系统。 活体成像和组织制图的新方法揭示了：细胞的行为是沿着 生殖带延伸过程中的背腹(DV)轴。DV行为调控在背化突变体中丢失。 这些发现挑战了这样一种假设，即诸如背部等远程TF只通过建立 控制压力的短期模式。为了检验长程热效应调制物理压力的假设 负责器官形状，我们建议：目标1测量器官级别的物理压力，并通过 与已知转铁蛋白表达模式的系统比较，确定背侧在器官尺度应激中的作用 协调。在目标2中，我们将扩展我们的观察范围，以研究细胞行为的协调 中肠环行过程中的异种组织层。 建议的研究将定量实验与理论相结合，以提供第一个策略 测量转铁蛋白介导的整体应力协调，形成器官。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 了解复杂的器官是如何形成的，包括环状结构。

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.