Control of Drosophila wing growth by morphogen

描述（由申请人提供）：该基金的主要目标是确定形态发生素如何控制动物发育过程中的器官生长。形态发生素是一种分泌的信号分子，通过发育中的组织传播并控制基因表达、模式、极性和生长。形态发生素的主要超家族在从海绵到人类的所有多细胞动物中都是保守的。了解它们的工作方式对人类健康具有巨大的意义，因为它们的活动和信号转导途径的遗传和环境扰动会导致各种发育和神经系统疾病以及广泛的癌症。因此，形态发生素的研究对于开发治疗人类疾病的诊断和治疗工具至关重要，这是NIH的中心使命。我们过去的研究，使用果蝇，有助于建立三个分泌蛋白超家族的成员，无翅/Ints（Wnts），骨形态发生蛋白（BMP）和刺猬（Hhs）都作为真正的形态发生蛋白。最初，这些研究集中在确定这些分子控制基因表达、模式和极性的逻辑和分子机制。在这里，我们转向更具挑战性的问题，即他们如何组织增长。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基于我们最近的发现，关于果蝇无翅（Wg），Wnt超家族的创始成员，如何控制发展中翅膀的急剧扩张，形态发生作用的经典范例。在该模型中，Wg和第二种形态发生素Decapentaplegic（Dpp）（一种BMP）共同作用以维持翼细胞的生长，并通过调节选择基因、残留基因（vg）和定义“翼”状态的转录因子的表达来将新细胞募集到翼原基中。我们有初步的证据表明，在这个过程中的关键事件是介导的一个单一的增强子元件的vg基因，它集成了Wg和Dpp输入，以及第三个“招聘”信号，依赖于保守的Warts-Hippo肿瘤抑制通路的瞬时激活。我们将结合联合收割机的遗传，转基因和分子的方法，以建立所有三个信号系统的作用，以及分子机制（S），他们是由这个增强子整合。此外，我们将分析形态发生剂依赖的翅膀生长的三个限制，即形态发生剂扩散的能力，JAK/Stat信号从周围组织的抑制作用，以及对系统类固醇激素蜕皮激素水平变化的依赖。这些实验将证实和推进我们控制器官生长的模型--这是所有动物都存在的一个基本的、未解决的问题--或者导致新的、可检验的假设。

DESCRIPTION (provided by applicant): 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 multi- cellular 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 neurological 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 more challenging problem 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), and a transcription factor that defines the "wing" state. We have preliminary 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. 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. In addition, we will analyze three limits to morphogen-dependent wing growth, namely the capacity of morphogens to spread, the inhibitory action of JAK/Stat signaling from surrounding tissue, and the reliance on changing levels of the systemic steroid hormone Ecdysone. These experiments will either confirm and advance our model for the control of organ growth- a fundamental, unsolved problem in all animals - or lead to new, testable hypotheses.