Regulation of SoxE Function During Neural Crest Formation

描述(申请人提供)：反复使用转录调节因子是胚胎发育的标志。数量相对较少的蛋白质必须参与决定器官和生物体形态的细胞命运的多样性。神经脊是一个很好的系统，在其中检查重复使用的发育调节蛋白。SOXE因子是一类关键的调节因子家族，调节神经脊内多种细胞的命运决定，包括前体细胞群的形成以及黑素细胞、软骨细胞和神经胶质细胞系的分化。这使得SoxE蛋白成为了解转录因子被重复利用来执行不同发育角色的分子机制的重要模型。本研究的目的是研究翻译后调控机制，如SUMO化，SoxE蛋白结构域的差异利用，以及与其他调控因子如SoxD蛋白和Wnt信号的相互作用，在SoxE功能调节中所起的作用。我们的研究表明，SoxE因子的相扑修饰对它们的发育功能有很大的影响，将它们从神经脊形成的促进剂转变为内耳形成的促进剂，这为本研究奠定了基础。我们在这些研究的基础上证明了SoxE因子是上下文相关的转录调节因子，并且相扑修饰通过促进Groucho家族共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相扑修饰改变SoxE功能的机制，以及Wnt信号、SoxD因子和特定的SoxE功能域如何影响这些因子的不同功能。这项拟议的研究旨在揭示控制SoxE功能的分子机制，并可能为其他重复利用的转录因子如何执行如此多样化的任务提供范例。由于SoxE特定的因子，以及更广泛的神经脊，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相关的问题。 与公共健康相关：本研究项目的目标是阐明E组Sox因子被调控的分子机制，并了解这种调控如何有助于它们在神经脊和其他组织中控制许多不同的发育决定。SoxE蛋白的神经脊和缺陷都与许多人类疾病和先天性疾病有关，阐明调控SoxE功能的分子机制对于了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.