Analysis of TGF-Beta/BMP-mediated Signaling During Drosophila Development

沃顿96-04769这项提案中概述的研究的长期目标是了解转化生长因子-β信号分子如何促进细胞之间的交流。细胞通讯对于多细胞生物体中细胞运动、生长和分化的正确表现是必不可少的。细胞信号分子转化生长因子-β超家族成员广泛存在于从线虫到人类的无脊椎动物和脊椎动物中。这些信号因子在发育过程中发挥的不同作用归因于这些配体的二聚性以及单体/单体的多种组合以及可能的配体/受体结合。在发育过程中，细胞必须接收和解释许多不同的信号，对于我们理解发育，我们必须阐明发生这一过程的过程。对于果蝇成员DPP来说，转化生长因子-β信号的发育后果和体内调控是最清楚的。为了确定两种不同的转化生长因子-β信号的功能，并研究它们的信号解释方法，沃顿博士迈出了第一步。他之前分离了果蝇的第二个成员--60A基因，对该基因进行了突变，并确定它对胚胎发育和成年肢体发育至关重要。在这项提案中，她打算通过1)通过产生马赛克克隆和分析突变表型来确定需要60A的组织，从而定义这些要求的细节。她将通过研究60A基因突变对中肠、成人眼睛和翅膀形成模式的重要基因的影响，来确定60A功能的发育后果。她还将研究这些基因对60A的调节。她将通过错误表达、突变克隆的产生和下游因素的分析来解决60A和DPP信号重叠的可能性。她打算研究60A信号的机制，并通过3)识别介导60A信号的组件，将其与已知的DPP信号进行比较。潜在的基因与已知的转化生长因子-β信号成分突变的相互作用将被研究。她的发现将为在发育中的有机体背景下细胞信号的动力学提供洞察力。了解转化生长因子-β信号因子的体内功能及其信号传递机制最终将有助于我们了解脊椎动物和无脊椎动物的基本过程。了解细胞信号的生物学是许多医学应用的核心，并最终将在疾病的预防和治疗中有用。

Wharton 96-04769 The long term goal of the research outlined in this proposal is to understand how TGF-Beta signaling molecules facilitate the communication between cells. Cellular communication is essential to the proper manifestation of cell movements, growth and differentiation in multi-cellular organisms. Members of the transforming growth factor-Beta (TGF-Beta) superfamily of cell signaling molecules are found in both invertebrates and vertebrates, from C.elegans to humans. The diverse roles performed by these signaling factors during development has been attributed to the dimeric nature of these ligands and the multiple combinations of monomer/monomer as well as ligand/receptor associations possible. During development cells must receive and interpret many different signals and it is essential to our understanding of development that we elucidate the process by which this occurs. The developmental consequences and in vivo regulation of TGF-Beta signaling are best understood for the Drosophila member, dpp. As a first step towards determining the functions of two different TGF-Beta signals and investigating the means by which their signals are interpreted, Dr. Wharton previously isolated a second member in Drosophila, the 60A gene, made mutations in the gene and determined that it is essential for embryogenesis and adult limb development. In this proposal, she intends to define the specifics of these requirements by 1) identifying the tissues in which 60A is required through the generation of mosaic clones and analysis of mutant phenotypes. She will 2) determine the developmental consequences of 60A function by examining the effect of 60A mutations on genes known to be important in patterning the midgut and the adult eye and wing. She will also examine the regulation of 60A by these genes. She will address the potential for overlap of 60A and dpp signaling using misexpression, generation of mutant clones and analysis of downstream factors. She intends to investigate the me chanism by which 60A signals and compare it to what is known for dpp signaling through 3) the identification of components mediating 60A signaling. Potential genetic interactions with mutations in known TGF-Beta signaling components will be investigated. Her findings will provide insight into the dynamics of cell signaling in the context of a developing organism. Understanding the in vivo function of TGF-Beta signaling factors and the mechanisms by which they signal will ultimately aid in our knowledge of fundamental processes in vertebrates, as well as in invertebrates. Understanding the biology of cell signaling is central to many medical applications and will ultimately be useful in the prevention and treatment of disease.