Regulation of SoxE Function During Neural Crest Formation

描述（由申请人提供）：反复使用转录调节因子是胚胎发育的标志。相对少量的蛋白质必须介导器官和生物体模式的细胞命运决定的多样性。神经嵴是一个很好的系统，其中检查反复使用的发育调节蛋白。SoxE因子是一个重要的调节因子家族，它介导神经嵴内多种细胞命运的决定，包括前体细胞群的形成和黑素细胞、软骨细胞和胶质细胞谱系的分化。这使得SoxE蛋白成为理解转录因子可重复利用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SUMOylation， 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功能的调节中发挥的作用。我们的研究表明，SUMO修饰SoxE因子对其发育功能有显著影响，使其从神经嵴形成的促进因子转变为内耳形成的促进因子，为本研究奠定了基础。在这些研究的基础上，我们证明了SoxE因子是依赖于环境的转录调控因子，SUMO修饰通过促进groucho家族共同抑制因子的招募，将它们转化为抑制因子。我们将采用体内和体外相结合的方法进一步研究SUMO修饰改变SoxE功能的机制，以及Wnt信号、SoxD因子和特定SoxE功能域如何促进这些因子的不同功能。该研究旨在揭示控制SoxE功能的分子机制，并可能作为其他重复利用的转录因子如何执行如此多样化的发育任务的范例。由于SoxE因子，特别是神经嵴，是许多疾病和先天性缺陷的基础，因此这项工作也将直接影响与人类健康相关的问题。

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.