Regulation and Scaling of a Morphogen Gradient

描述(由申请人提供)：形态生成概念是发育生物学的核心概念。形态分子形成浓度梯度，为细胞场提供位置信息。这一应用将集中在实验研究上，以推进形态生成的概念。双核果蝇形态原梯度(BCD)通过以浓度依赖的方式直接激活其下游靶基因来指导前后(AP)图案形成。尽管BCD在AP模式形成中的作用已经得到了很好的证实，但控制这一过程的调控网络还没有完全了解。例如，对BCD梯度系统的运行和调节至关重要的几个方面，例如BCD降解、翻译后修饰和BCD在物种内的梯度伸缩，目前几乎仍然未知。这一应用的总体假设是，调控网络使BCD能够在梯度形成之前和期间以及在其作为转录激活因子的作用时对各种输入做出反应。监管网络的这三层是在三个具体目标下调查的。目的1将通过MAPK和其他控制BCD降解的调节因子的作用来研究调节BCD梯度形成的机制。目的2将通过BCD与MAPK的相互作用以及翻译后修饰的作用来研究BCD作为激活剂的作用机制。目标3将研究导致BCD比例梯度的机制，并将分析卵子发生过程中的调节层在控制稍后胚胎中粗壮和规模的AP模式中的作用。这项拟议的研究建立在强有力的初步研究基础上，并通过实验室最近建立的一套量化工具使其成为可能。这项拟议的研究将对我们理解形态梯度如何发挥作用以及如何实现发育稳健性的努力产生强大而持久的影响。这项拟议的研究对人类健康也很重要，因为形态基因和MAPK信号转导从根本上与出生缺陷有关，此外，该项目中研究的一个基因的人类同源基因与中耳炎有关，中耳炎是儿童耳聋的主要原因。 公共卫生相关性：拟议的工作解决了进化和发育生物学中的一个基本问题，即胚胎模式是如何以规模化和健壮的方式形成的。它的目的是在定量、系统的水平上剖析复杂的调控网络控制模式的形成，这些信息将是我们理解导致出生缺陷的人类遗传疾病的基础。

DESCRIPTION (provided by applicant): The morphogen concept is central to developmental biology. Morphogen molecules form concentration gradients to provide positional information to a field of cells. This application will focus on experimental studies to advance the morphogen concept. The Drosophila morphogen gradient of Bicoid (Bcd) instructs anterior- posterior (AP) patterning by directly activating its downstream target genes in a concentration-dependent manner. Although the role of Bcd in AP patterning is well established, the regulatory network controlling this process is not fully understood. For example, several aspects critical to the operation and regulation of the Bcd gradient system, e.g., Bcd degradation, post-translational modifications, and Bcd gradient scaling within a species, remain virtually unknown at this time. The overall hypothesis of this application is that a regulatory network enables Bcd to respond to various inputs, both before and during the time of gradient formation, and at the time of its action as a transcriptional activator. These three layers of the regulatory network are investigated in three specific aims. Aim 1 will study the mechanisms that regulate Bcd gradient formation by focusing on the role of MAP kinase (MAPK) and other regulators that control Bcd degradation. Aim 2 will investigate the mechanisms that regulate the action of Bcd as an activator by focusing on its interaction with MAPK and the roles of post-translational modifications. Aim 3 will investigate the mechanisms leading to a scaled Bcd gradient and will analyze the layer of regulation during oogenesis for its role in controlling the robust and scaled AP patterning later in embryos. The proposed study is based on strong preliminary studies and is made possible by a set of quantitative tools recently established in the lab. The proposed study will have powerful and sustained impact on our efforts to understand how morphogen gradients work and how developmental robustness is achieved. The proposed study is also important to human health because morphogens and MAPK signaling are fundamentally relevant to birth defects and, furthermore, the human homologue of a gene studied in this project has been implicated in otitis media, a leading cause of childhood deafness. PUBLIC HEALTH RELEVANCE: The proposed work addresses a fundamental question in evolutionary and developmental biology, namely, how embryonic patterns are formed in a scaled and robust manner. It aims at dissecting the intricate regulatory network controlling pattern formation at a quantitative, systems level, information that will be fundamental to our ability to understand human genetic disorders that cause birth defects.