Pattern Formation in the Wing of Drosophila

项目概要-果蝇翅膀的模式形成（S.S. 1）智力优势-胚胎的正常发育需要特定组织类型的精确规格，而这种规格的失败是许多出生缺陷和先天性疾病的基础。 在发育过程中，组织和细胞之间的信号传递通常在这一过程中起着关键作用。 然而，许多重要信号通路的细节以及这些信号如何在发育中的组织中传输仍然知之甚少。 该项目研究了由BMP类TGF β介导的重要信号长距离传输的方式，以及该信号如何被细胞外蛋白质修饰。 用于这项工作的模型系统是果蝇的翅膀。 这个模型系统有几个优点：果蝇的遗传和分子分析可能是任何其他动物都无法比拟的，果蝇翅膀发育的机制与人类和其他哺乳动物的机制有几个惊人的相似之处。 这项工作特别关注翅膀内横脉的发展，以及两个BMP样信号分子所扮演的角色（Decapentaplegic和玻璃底船），三种结合BMP的蛋白质，（短原肠胚形成，扭曲原肠胚形成-2，Crossveinless 2），和蛋白酶托尔金，它可以通过切割它来调节短原肠胚形成的活性。提案中概述的证据表明，横脉，与其他静脉不同的是，它的初始发育需要BMP的形成。 此外，横脉对BMP信号的一个不寻常的方面非常敏感：BMP结合分子刺激长距离信号。 这些分子最为人所知的是它们通过将BMP与其受体隔离而作为信号传导抑制剂的能力。 尽管如此，初步数据显示BMP结合分子是横脉中信号传导所必需的。 目的1研究这些分子的作用方式，详细研究它们在哪里需要，它们作用于哪种配体，以及它们如何影响BMP扩散。 目的2检测Crossveinless 2蛋白，验证其在体内和体外对短原肠胚形成功能的影响。 目的3描述影响横脉发育的新的遗传位点。 2)更广泛的影响。 资助的研究将与那些从事脊椎动物和无脊椎动物发育生物学的人明显相关。 这项研究也有助于培养研究生和本科生。 PI的实验室通常每年支持4-5名研究生和2-3名本科生，这些人承担了研究的主要任务。 后者不仅参与独立的学习课程，而且还在PI的实验室中轮换，作为威斯康星大学麦迪逊分校生物学入门课程的一部分。 这些学生中的许多人都在生物科学领域从事富有成效的职业，如研究生，博士后或教师。 PI也大量参与本科教育，这种教学在很大程度上是由PI的研究计划。 PI还积极参与撰写该领域的评论，并反过来充当手稿和赠款的裁判。 PI维护一个详细介绍果蝇免疫组织学和镶嵌技术的网站，作为该领域新技术人员的指南（http：//bender.zoology.wisc.edu/antiweb.html）。

Project Summary- Pattern formation in the wing of Drosophila (S.S. Blair, PI)1) Intellectual Merit- The normal development of embryos requires the precise specification of specific tissue types, and failures in that specification underlie many birth defects and congenital diseases. Signaling between tissues and cells during development often plays a critical role in this process. However, the details underlying many important signaling pathways and how those signals are transmitted in developing tissues is still quite poorly understood. This project examines the way in which important signals, mediated by the BMP class of TGFbs, are transmitted over long distance, and how that signaling is modified by extracellular proteins. The model system used for this work is the wing of the fruitfly, Drosophila melanogaster. The advantages of this model system are several: the genetic and molecular analyses possible in Drosophila are perhaps unmatched by any other animal, and the mechanisms underlying development of the Drosophila wing shows several striking parallels with the mechanisms used in humans and other mammals. The work focuses specifically on the development of the crossveins within the wing, and the role played by two BMP-like signaling molecules (Decapentaplegic and Glass bottom boat), three proteins that bind BMPs, (Short gastrulation, Twisted gastrulation-2, Crossveinless 2), and the protease Tolkin, which can regulate the activity of Short gastrulation by cleaving it.The evidence outlined in the proposal indicates that the crossveins, unlike the other veins, require BMP formation for their initial development. Moreover, the crossveins are exquisitely sensitive to an unusual aspect of BMP signaling: the stimulation of long-distance signaling by BMP-binding molecules. These molecules are best known for their ability to act as inhibitors of signaling by sequestering BMPs from their receptors. Nonetheless, preliminary data shows that the BMP-binding molecules are required for signaling in the crossveins. Aim 1 examines the way in which these molecule act, examining in detail where they are required, which ligand they act upon, and how they affect BMP diffusion. Aim 2 examines the Crossveinless 2 protein, testing theories that it acts on Short gastrulation function in vivo and in vitro. Aim 3 characterizes novel genetic loci that affect crossvein development. 2) Broader impact. The research funded will be of obvious relevance to those working on developmental biology of vertebrates and invertebrates. This research also helps train both graduate students and undergraduates. The PI's lab usually supports 4-5 graduate students and 2-3 undergraduates per year, and these carry out the brunt of the research. The latter are involved not only in independent study classes, but also rotate through the PI's lab as part of the introductory biology sequence at the University of Wisconsin-Madison. Many of these students have gone on to productive careers in the biosciences, as graduate students, postdocs or faculty. The PI is also heavily involved in undergraduate education, and this teaching is heavily informed by the PI's research program. The PI has also been very involved in writing reviews for the field and in turn as acting as a referee for manuscripts and grants. The PI maintains a web site detailing techniques for immunohistological and mosaic techniques in Drosophila as a guide for those new to the field (http://bender.zoology.wisc.edu/antiweb.html).