Regulation of SoxE Function During Neural Crest Formation

描述（由申请人提供）：转录调节因子的重复使用是胚胎发育的标志。相对少量的蛋白质必须介导细胞命运决定的多样性，这些决定器官和生物体的模式。神经嵴是一个很好的系统，在其中检查发育调节蛋白的重复使用。SoxE因子是调节因子的关键家族，其介导神经嵴内的多个细胞命运决定，包括黑素细胞、软骨和神经胶质细胞谱系的前体群体的形成和分化。这使得SoxE蛋白成为理解转录因子可以重复利用以执行不同发育角色的分子机制的重要模型。本研究项目的目标是研究翻译后调节机制如SUMO化，SoxE蛋白结构域的差异利用以及与其他调节因子如SoxD蛋白和Wnt信号的相互作用，在SoxE功能的调节中发挥作用。这项调查的基础已经奠定了我们的研究表明，SUMO修饰的SoxE因子有显着的影响，他们的发育功能，开关从神经嵴形成的启动子，内耳形成的启动子。我们已经建立在这些研究的基础上，证明SoxE因子是上下文依赖性转录调节因子，SUMO修饰通过促进groucho家族共阻遏物的招募将它们转化为阻遏物。我们将结合体内和体外方法进一步研究SUMO修饰改变SoxE功能的机制，并研究Wnt信号、SoxD因子和特定的SoxE功能结构域如何促进这些因子的不同功能。拟议的研究旨在揭示控制SoxE功能的分子机制，并可能作为其他粘附性利用的转录因子如何进行这种多样化的任务发展的范例。由于SoxE因子特别是神经嵴更普遍地是一大群疾病和先天性缺陷的基础，这项工作也将直接影响与人类健康有关的问题。 公共卫生相关性：该研究项目的目标是阐明E组Sox因子被调节的分子机制，并了解这种调节如何有助于它们控制神经嵴和其他组织中许多不同发育决定的能力。SoxE蛋白的神经嵴和缺陷都与许多人类疾病和先天性疾病有关，阐明调节SoxE功能的分子机制对于理解这些疾病的发病机制至关重要。

DESCRIPTION (provided by applicant): The reiterative use of transcriptional regulatory factors is a hallmark of embryonic development. A relatively small number of proteins must mediate the multiplicity of cell fate decisions that pattern organs and organisms. The neural crest is an excellent system in which to examine the reiterative use of developmental regulatory proteins. SoxE factors are a key family of regulatory factors that mediate multiple cell fate decisions within the neural crest including the formation of the precursor population and differentiation of the melanocyte, cartilage and glial cell lineages. This makes SoxE proteins an important model for understanding the molecular mechanisms by which transcription factors can be repeatedly utilized to carry out diverse developmental roles, The goal of this research project is to investigate the roles that post-translational regulatory mechanisms such as SUMOylation, the differential utilization of SoxE protein domains, and interactions with other regulatory factors such as SoxD proteins and Wnt signals, play in the modulation of SoxE function. The foundation for this investigation has been laid by our studies demonstrating that SUMO modification of SoxE factors has a dramatic effect on their developmental function, switching them from promoters of neural crest formation to promoters of inner ear formation. We have built on these studies by demonstrating that SoxE factors are context dependent transcriptional regulators, and that SUMO modification converts them to repressors by facilitating the recruitment of groucho family co-repressors. We will use a combination of in vivo and in vitro approaches to further investigate the mechanisms via which SUMO modification alters SoxE function, as well as investigate how Wnt signals, SoxD factors, and specific SoxE functional domains contribute to the diverse functions of these factors. The proposed research is designed to reveal the molecular mechanisms that govern SoxE function and that may serve as paradigms for how other reiteratively utilized transcription factors can carry out such a diverse developmental of tasks. Because SoxE factors specifically, and the neural crest more generally, underlie a large group of diseases and congenital defects, this work will also directly impact issues related to human health. PUBLIC HEALTH RELEVANCE: The goal of this research project is to elucidate the molecular mechanisms via which Group E Sox factors are regulated, and to understand how this regulation contributes to their ability to control numerous distinct developmental decisions in the neural crest and other tissues. Both the neural crest and defects in SoxE proteins are linked to a number of human diseases and congenital disorders, and elucidating the molecular mechanisms regulating SoxE function is essential to understanding the pathogenesis of these disorders.