Proximo-Distal Patterning in the Drosophila Appendages

描述(申请人提供)：动物的发育依赖于细胞命运和细胞潜能的不断完善。例如，胚胎干细胞是多能的，但它们的后代逐渐承担起更具体的命运，这取决于它们感知的细胞外线索和它们表达的内在因素。在机制层面上了解这一过程对于最终利用干细胞用于医学的潜力以及理解许多疾病，如癌症，这一过程未能得到适当调控的疾病非常重要。本课题所研究的模型系统是果蝇的附肢规范。一个目标是在分子水平上了解最初的腿和翅膀原基是如何在早期胚胎中建立起来的。第二个目标是描述在腿部近端-远端轴形成过程中，顺式调节增强子元件整合信号和转录因子输入的机制。第三个目标是研究表皮生长因子通路如何在腿的最远端建立位置信息。总而言之，这些目标将为如何首先指定附肢以及如何实现腿部的最终位置信息提供重要的见解。 与公共卫生相关：这个项目解决了动物发育的基本过程，特别是细胞如何随着发育的进行而逐渐限制其潜力。例如，干细胞是多能的，但它们的一些后代的潜力更有限。当这一过程没有得到适当的调控时，可能会导致发育缺陷和癌症。

DESCRIPTION (provided by applicant): Animal development depends on the successive refinement of cell fates and cell potentials. Embryonic stem cells, for example, are pluripotent but their descendents gradually take on more specific fates depending on the extracellular cues they perceive and intrinsic factors they express. Understanding this process at a mechanistic level is important for eventually harnessing the potential of stem cells for medicine, as well as for understanding many diseases, such as cancers, where this process fails to be properly regulated. In this project, the model system to be investigated is appendage specification in the fruit fly, Drosophila melanogaster. One goal is to understand, at a molecular level, how the initial leg and wing primordia become established in the early embryo. A second goal is to characterize the mechanism by which cis-regulatory enhancer elements integrate signaling and transcription factor inputs during the formation of the proximal- distal axis in the leg. A third goal is to investigate how the Epidermal Growth Factor pathway establishes positional information in the distal-most segments of the leg. Together, these Aims will provide significant insights into how appendages are first specified to how final positional information in the leg is achieved. PUBLIC HEALTH RELEVANCE: This project addresses fundamental processes during animal development, in particular, how cells gradually restrict their potentials as development proceeds. Stem cells, for example, are pluripotent, but some of their descendents have more limited potentials. When this process is not properly regulated, developmental defects and cancers can result.