Control of Drosophila wing growth by morphogen

描述(申请者提供)：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，在发育中的组织中传播，控制基因的表达、模式、极性和生长。形态原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。了解它们是如何工作的对人类健康具有巨大的影响，因为它们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疾病以及各种癌症。因此，对形态原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，这是美国国立卫生研究院的中心任务。我们过去利用果蝇的研究帮助建立了三个超家族分泌蛋白的成员，Wingless/Ints(Wnts)，BMPs和Hedgehog(HHS)都具有真正的形态发生功能。最初，这些研究的重点是确定这些分子控制基因表达、模式和极性的逻辑和分子机制。在这里，我们转向一个更具挑战性的问题，即它们如何组织增长。在拟议的研究中，我们将测试和扩展我们假设的一个新的增长模型，该模型基于我们最近的发现，即WnT超家族的创始成员之一果蝇Wingless(Wg)如何控制发育中的翅膀的戏剧性扩张，这是形态生成剂作用的经典范例。在这个模型中，Wg和第二个形态发生因子Decapentaplegic(DPP)BMP共同作用，通过调节选择器基因vestigial(Vg)和定义“翅膀”状态的转录因子的表达，维持翅膀细胞的生长，并将新细胞招募到翅膀原基。我们有初步证据表明，在这一过程中的关键事件是由VG基因中的单个增强子元件介导的，该元件整合了Wg和DPP输入，以及依赖于保守的WARTS-HIPPO肿瘤抑制通路的瞬时激活的第三个“招募”信号。我们将结合遗传、转基因和分子方法来确定所有这三个信号系统的作用，以及它们被这个增强子整合的分子机制(S)。此外，我们将分析依赖形态激素的翅膀生长的三个限制，即形态原扩散的能力，来自周围组织的JAK/STAT信号的抑制作用，以及对系统类固醇激素蜕皮激素水平变化的依赖。这些实验要么将证实并推进我们的器官生长控制模型--这是所有动物都面临的一个根本的、尚未解决的问题--要么将导致新的、可验证的假说。

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.