Regulation and Scaling of a Morphogen Gradient

描述（由申请人提供）：形态发生的概念是发育生物学的核心。形态形成分子形成浓度梯度，为细胞场提供位置信息。本应用程序将着重于实验研究，以推进形态发生的概念。果蝇Bicoid的形态发生梯度（Bcd）通过直接激活其下游靶基因，以浓度依赖性的方式指导前后（AP）模式。虽然Bcd在AP模式中的作用已经确立，但控制这一过程的调控网络尚未完全了解。例如，对Bcd梯度系统的运行和调控至关重要的几个方面，如Bcd降解、翻译后修饰和物种内Bcd梯度缩放，目前几乎仍然未知。该应用的总体假设是，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响应各种输入。监管网络的这三层有三个具体目的。目的1将研究调节Bcd梯度形成的机制，重点关注MAP激酶（MAPK）和其他控制Bcd降解的调节因子的作用。目的2将通过关注Bcd与MAPK的相互作用以及翻译后修饰的作用来研究Bcd作为激活剂的调节机制。目的3将研究导致规模化Bcd梯度的机制，并分析卵子发生过程中的调控层，以了解其在胚胎后期控制稳健和规模化AP模式中的作用。这项拟议的研究是基于强有力的初步研究，并通过实验室最近建立的一套定量工具使之成为可能。这项研究将对我们理解形态梯度如何工作以及发育稳健性如何实现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，因为形态因子和MAPK信号传导与出生缺陷有着根本的关系，此外，该项目中研究的一个基因的人类同源物与中耳炎有关，中耳炎是儿童耳聋的主要原因。

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.