Regulation and Scaling of a Morphogen Gradient

描述（由申请人提供）：形态原概念是发育生物学的核心。形态发生素分子形成浓度梯度以向细胞场提供位置信息。这项申请将集中在实验研究，以推进形态发生的概念。Bicoid（Bcd）的果蝇形态发生梯度通过以浓度依赖性方式直接激活其下游靶基因来指导前后（AP）模式化。虽然Bcd在AP模式中的作用已经很好地确定，但控制这一过程的调节网络尚未完全了解。例如，对于Bcd梯度系统的操作和调节至关重要的几个方面，例如，Bcd降解，翻译后修饰，和Bcd梯度缩放在一个物种内，仍然几乎未知在这个时候。本申请的总体假设是，调节网络使Bcd能够在梯度形成之前和期间以及在其作为转录激活剂的作用时对各种输入做出响应。这三个层次的监管网络进行了调查，在三个具体目标。目的1通过研究MAP激酶（MAPK）等调控Bcd降解的调节因子，探讨Bcd梯度形成的调控机制。目的二是通过研究Bcd与MAPK的相互作用以及翻译后修饰的作用，探讨Bcd作为活化剂的作用机制。目标3将研究导致Bcd梯度缩放的机制，并分析卵子发生过程中的调节层，以确定其在控制胚胎后期稳健且缩放的AP模式中的作用。拟议的研究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成为可能。这项研究将对我们理解形态梯度如何工作以及如何实现发育稳健性产生强大而持续的影响。拟议的研究对人类健康也很重要，因为形态发生素和MAPK信号传导与出生缺陷基本相关，此外，该项目中研究的基因的人类同源物与中耳炎有关，这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，即胚胎模式如何以规模化和稳健的方式形成。它的目的是解剖复杂的调控网络控制模式的形成在定量，系统水平，信息将是我们的能力，了解人类遗传疾病，导致出生缺陷的基础。

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.