Morphogen control of organ growth in Drosophila

项目摘要 这项资助的主要目标是确定在动物发育过程中，形态生物质如何控制器官生长。 形态原是分泌的信号分子，通过发育中的组织和控制基因传播。 表达、模式、极性和生长。形态生物质的主要超家族在所有 多细胞动物，从海绵到人类。了解它们是如何工作的对 人类健康，作为其活动和信号转导途径的遗传和环境扰动 导致各种发育和生理障碍以及多种癌症。研究与实践 因此，形态生物质对于开发治疗人类疾病的诊断和治疗工具至关重要，这是一种核心的 美国国立卫生研究院的使命。 我们过去用果蝇进行的研究，有助于确定三个成员 分泌蛋白超家族，无翼/Ints(Wnts)，骨形成蛋白(BMPs)和 刺猬(HHS)的所有功能都是真正的形态原。最初，这些研究的重点是确定 这些分子控制基因表达、模式和基因的逻辑和分子机制 两极。在这里，我们转向他们如何组织增长的根本和持久的谜团。 在拟议的研究中，我们将测试和扩展我们基于最近的 关于WnT超家族的创始成员果蝇Wingless(Wg)如何控制 发展中的翅膀戏剧性地扩张，这是形态生成作用的经典范例。在此模型中，Wg和a 第二形态发生蛋白是一种骨形态发生蛋白，它共同作用于维持翼细胞的生长和 通过调节选择器基因vestigial(VG)的表达将新细胞招募到翼原基中 定义“翅膀”状态的转录因子。我们有证据表明，这一过程中的关键事件是 由Vg基因中的一个增强子元件介导，它整合了Wg和DPP输入，以及第三个 依赖于保守的肿瘤抑制因子WARTS-HIPPO瞬时激活的“重新招募”信号 途径及其转录效应约克(yki，a yap)。我们将把基因、转基因和分子技术结合起来 确定所有三个信号系统的作用以及分子机制的方法(S) 它们被这个增强器整合在一起。我们还将寻求澄清工作组和民进党如何通过组织 以达到适当的范围，并确定负责终止生长的机制(S)何时 机翼达到了正确的大小。最后，我们将询问我们在翼中阐明的原则是否可以 推广到飞行中的其他器官系统。

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.