Morphogen control of organ growth in Drosophila

项目摘要 这项资助的主要目标是确定形态发生素如何在动物发育过程中控制器官生长。 形态发生素是一种分泌的信号分子，通过发育中的组织和控制基因传播 表达、模式、极性和生长。形态发生素的主要超家族在所有形态发生素中都是保守的。 多细胞动物，从海绵到人类。了解它们的工作原理对我们有着巨大的意义， 人类健康，因为其活动和信号传导途径的遗传和环境扰动 导致多种发育和生理障碍以及多种癌症。研究 因此，形态发生素对于开发治疗人类疾病的诊断和治疗工具至关重要， NIH的使命。 我们过去的研究，使用果蝇，有助于建立三个成员， 分泌蛋白超家族，无翅/Ints（Wnts），骨形态发生蛋白（BMP）和 刺猬（Hhs）都是真正的形态发生素。最初这些研究的重点是确定 这些分子控制基因表达、模式和 极性在这里，我们转向他们如何组织增长的基本和持久的奥秘。 在拟议的研究中，我们将测试和扩展一个新的模型，我们已经假设的增长，根据我们最近的 无翅果蝇（Wg）是Wnt超家族的创始成员， 发育中的翅膀戏剧性地扩张，这是形态发生作用的经典范例。在该模型中，Wg和a 第二种形态发生素Decapentaplegic（Dpp），一种BMP，共同作用以维持翅膀细胞的生长， 通过调节选择基因vg的表达， 转录因子，定义了“翅膀”的状态。我们有证据表明这个过程中的关键事件是 由整合Wg和Dpp输入的vg基因中的单个增强子元件介导，以及第三个增强子元件介导。 依赖于保守的Warts-Hippo肿瘤抑制因子瞬时激活的“募集”信号 途径及其转录效应物Yorki（Yki，一种雅普）。我们将联合收割机结合遗传、转基因和分子 建立所有三种信号系统的作用以及分子机制的方法， 它们被这个增强子整合。我们还将寻求澄清Wg和Dpp如何通过组织移动 以达到适当的范围，并确定负责终止增长的机制， 机翼达到正确的尺寸。最后，我们会问，我们在机翼上阐明的原则是否可以 推广到苍蝇的其他器官系统。

Project Summary The main goal of this grant is to determine how morphogens control organ growth during animal development. Morphogens are secreted signaling molecules that spread through developing tissues and control gene expression, pattern, polarity and growth. The major superfamilies of morphogens are conserved in all multicellular animals, from sponges to man. Understanding how they work has enormous implications for human health, as genetic and environmental perturbations of their activities and signal transduction pathways cause diverse developmental and physiological disorders as well as a wide range of cancers. Research on morphogens is thus critical for developing diagnostic and therapeutic tools to treat human disease, a central mission of the NIH. Our past studies, using Drosophila, were instrumental in establishing that members of three superfamilies of secreted proteins, Wingless/Ints (Wnts), Bone Morphogenetic Proteins (BMPs) and Hedgehogs (Hhs) all function as bona fide morphogens. Initially these studies were focused on determining both the logic and molecular mechanisms by which these molecules control gene expression, pattern and polarity. Here, we turn to the fundamental and enduring mystery of how they organize growth. In the proposed research, we will test and extend a new model we have posited for growth based on our recent discoveries about how Drosophila Wingless (Wg), a founding member of the Wnt superfamily, controls the dramatic expansion of the developing wing, a classic paradigm for morphogen action. In this model, Wg and a second morphogen Decapentaplegic (Dpp), a BMP, act together to sustain the growth of wing cells and to recruit new cells into the wing primordium by regulating expression of the selector gene, vestigial (vg), a transcription factor that defines the “wing” state. We have evidence that the key events in this process are mediated by a single enhancer element in the vg gene, which integrates Wg and Dpp input, as well as a third “recruitment” signal that depends on transient activation of the conserved Warts-Hippo tumor suppressor pathway and its transcriptional effector Yorki (Yki, a YAP). We will combine genetic, transgenic and molecular approaches to establish the roles of all three signaling systems, as well as the molecular mechanism(s) by which they are integrated by this enhancer. We will also seek to clarify how Wg and Dpp move through tissue to achieve the appropriate range, and to determine the mechanism(s) responsible for terminating growth when the wing reaches the correct size. Finally, we will ask if the principles we elucidate in the wing can be generalized to other organ systems in the fly.