Proximo-distal patterning in the Drosophila appendages

描述(申请人提供)：该项目的长期目标是了解细胞间信号系统如何在发育过程中与区域表达的转录因子相互作用，以产生正确的比例和图案的身体部分。将使用的实验系统是果蝇，黑腹果蝇。这些实验的起点是两个基因，同胸和牙外，这两个基因对于确定苍蝇附属物近端的身份很重要。这些基因似乎限制或改变了已知的在附肢发育过程中运行的信号通路的活动。牙外和同胸都编码含有同源结构域的转录因子。然而，牙外蛋白只有在同胸的情况下才是核的。在几个组织中，同胸和牙外环与由teashirt基因编码的含锌指的转录因子共表达，并且在眼睛中，这三种蛋白与由失眼基因编码的另一同源域蛋白共表达。本资助期的具体目标是：(1)确定同胸控制牙外核定位的机制，(2)表征同胸和teashirt在翅膀和眼睛发育中的作用，(3)表征在腿发育过程中参与抑制hth表达的基因，以及(4)通过正向遗传筛选鉴定新基因的作用，在苍蝇附属物的近端-远端图案中。同胸和牙外都有脊椎动物的同源物，当错误表达时，可能会导致白血病，这表明它们也在调节脊椎动物的生长和发育中发挥作用。此外，在脊椎动物和苍蝇肢体发育中，这些因子的转录和转录后调控似乎相似，这表明它们的许多功能也可能是保守的。因此，了解它们在果蝇发育中的基本功能应该会产生与白血病相关的信息，以及可能发生在脊椎动物肢体发育中的缺陷。

DESCRIPTION (provided by applicant): The long-term goals of this project are to understand how cell-to-cell signaling systems interface with regionally expressed transcription factors during development to generate correctly proportioned and patterned body parts. The experimental system that will be used is the fruit fly, Drosophila melanogaster. The starting point for these experiments are two genes, homothorax and extradenticle, that are important for specifying the identity of the proximal portion of the appendages in flies. These genes appear to limit or modify the activities of signaling pathways known to operate during appendage development. Both extradenticle and homothorax encode homeodomain-containing transcription factors. However, Extradenticle protein is only nuclear in the presence of Homothorax. In several tissues, Homothorax and Extradenticle are co-expressed with a Zn-finger-containing transcription factor encoded by the teashirt gene and, in the eye, these three proteins are co-expressed with another homeodomain protein encoded by the eyeless gene.The specific aims for this funding period are to: (1) determine the mechanism by which Extradenticle's nuclear localization is controlled by Homothorax, (2) characterize the roles of homothorax and teashirt in wing and eye development, (3) characterize the genes involved in repressing hth expression during leg development, and (4) characterize the role of novel genes, identified by a forward genetic screen, in proximo-distal patterning in the fly appendages. homothorax and extradenticle both have vertebrate homologs that, when misexpressed, can contribute to leukemias, suggesting that they also play a role in regulating growth and development in vertebrates. In addition, the transcriptional and post-transcriptional regulation of these factors appears similar in vertebrate and fly limb development, suggesting that many of their functions may also be conserved. An understanding of their basic functions in fly development should therefore generate information that is relevant to leukemia, as well as to defects that can occur in vertebrate limb development.