成形素和基因调控网络是发育生物学的两个核心概念。成形素蛋白分子形成浓度梯度给特定区域的细胞提供基因表达、分化和发育的位置信息，基因调控网络整合来自上游的位置信息从而形成特定的表达模式。以定量和系统地解析胚胎前后轴线上发育模式建立的调控机制为目标，本项目拟从三个层次全面阐释果蝇早期胚胎中Bicoid转录调控系统：1.F-box蛋白和Torso/MAPK信号通路在Bicoid蛋白梯度形成中的功能；2.这些因子对Bicoid转录因子活性的影响；3.构建Bicoid梯度介导的调控网络的在群体内、物种内和物种间不同水平的演化模型。应用一系列体内外的实验手段，本项目将整合上游蛋白质修饰和调节信号的数据、Bicoid动态变化的数据和下游间隙基因相互作用的数据，剖析胚胎发育模式的鲁棒性和尺度性的基本生物学问题。

Mechanistic understanding of human genetic disorders that cause birth defects requires fundamental knowledge of both the sensitive and robust aspects of developmental processes. The proposed work seeks to dissect the intricate regulatory network controlling embryonic pattern formation at a quantitative, systems level. The morphogen concept is central to developmental biology. Morphogen molecules form concentration gradients to provide positional information to a field of cells. We propose to perform quantitative studies to dissect the molecular mechanisms of anterior-posterior (AP) patterning controlled by the morphogen gradient of Bicoid (Bcd) and excecuted by the gap gene regulatory network in the Drosophila embryo. The overall hypothesis of this application is that a multi-layered regulatory network enables Bcd to respond to, and interact with, various other regulatory inputs to control the dynamics of pattern formation. These layers of regulation are both before and during the time of gradient formation, and at the time of its action as a transcriptional activator. We will study the mechanisms that regulate Bcd gradient formation by focusing on the roles of F-box proteins and the MAP kinase (MAPK) pathway. We will also investigate the mechanisms that regulate the action of Bcd as a transcriptional activator by focusing on its interaction with F-box proteins and the MAPK pathway and the roles of post-translational modifications. We will also investigate the mechanistic origins of the formation of a Bcd gradient and its regulatory consequences by unifying the results of three distinct evolutionary scales: within-population, within-species and between-species. The proposed study is based on strong preliminary studies and is made possible by a set of quantitative tools recently established in our lab. It will have powerful and sustained impact on our efforts to understand how morphogen gradients work and how developmental robustness is achieved.