Proximo-distal Patterning inthe Drosophila appendeges

描述(申请人提供)：多细胞动物的发育需要细胞-细胞信号通路和细胞类型特定转录因子的协调活动。在这个项目中，这些输入是如何在动物附肢的发展过程中被协调的将被调查。以黑腹果蝇为模型系统，重点研究了无翼(Wg)和骨形态发生蛋白同源物十叉神经麻痹(DPP)这两条信号通路如何形成腿的近端-远端(PD)轴。以前的工作证实，Wg和DPP结合在一起，可以在PD轴上的特定位置激活靶基因的转录。然而，这些信号如何转化为转录激活尚不清楚。利用报告基因和DNA结合分析，将研究PD基因是如何沿着PD轴被激活的。其次，将使用一种新的方法来分析PD基因调控序列的染色质结构。第三，研究细胞增殖动力学在PD基因调控中的作用。这些研究将在几个方面影响公众健康。首先，分泌信号激活基因表达的机制在动物发育和疾病的许多方面都是共同的。因此，更好地了解这些基本机制对于破译这些途径在改变时如何导致癌症等疾病至关重要。其次，许多人类的出生缺陷是由于附肢的发育问题造成的。由于许多控制附肢发育的转录因子、信号分子和潜在机制在果蝇和人类之间是保守的，在果蝇等实验强大的系统中更全面地剖析这些过程可能会为了解这些人类出生缺陷提供重要的见解。

DESCRIPTION (provided by applicant): The development of multicellular animals requires the coordinated activities of cell-cell signaling pathways and cell-type specific transcription factors. In this project, how these inputs are orchestrated during the development of animal appendages will be investigated. Using Drosophila melanogaster as the model system, the focus is how two signaling pathways, Wingless (Wg) and the BMP homolog Decapentaplegic (Dpp), create the proximo-distal (PD) axis of the leg. Previous work established that Wg and Dpp combine to activate the transcription of target genes at discreet positions along the PD axis. However, how these signals translate to transcriptional activation is not understood. Using reporter gene and DNA binding analyses, how PD genes are activated along the PD axis will be investigated. Second, a novel method to analyze the chromatin structure of PD gene regulatory sequences will be employed. Third, the role that cellular proliferation dynamics play in PD gene regulation will be investigated. These studies will impact public health in several ways. First, the mechanism by which secreted signals activate gene expression is common to many aspects of animal development and disease. Thus, a better understanding of these basic mechanisms is critical for deciphering how these pathways, when altered, contribute to diseases such as cancer. Second, many human birth defects are due to problems in the development of the appendages. As many of the transcription factors, signaling molecules, and underlying mechanisms controlling appendage development are conserved between Drosophila and humans, it is likely that a more comprehensive dissection of these processes in an experimentally powerful system such as Drosophila will provide important insights into these human birth defects.