The Role of SoxE Transcription Factors in Neural Crest Cell Specialization

项目总结/摘要 神经损伤是一类综合征，其主要特征是脑内畸形。 颅面复合体这些缺陷是由神经嵴（一种干细胞）的异常发育引起的 脊椎动物特有的种群。神经嵴的一个显著特征是它们能够同时产生 外胚间充质（骨/软骨）和非外胚间充质（黑素细胞和外周神经元/神经胶质） 衍生物. SoxE转录因子在肿瘤细胞的形成和分化中起重要作用。 神经嵴。所有三种SoxE因子（Sox 8、Sox 9和Sox 10）都有冗余功能， 阵有趣的是，个别的SoxE因子指导神经嵴分化成不同的谱系。 Sox 9促进软骨形成，而Sox 10支持黑素细胞和外周神经元/神经胶质细胞的命运。一个 一个突出的问题是这些高度相似的SoxE因子如何导致神经嵴特化。这项建议 利用基于组学的方法、功能获得和丧失实验以及Sox 9-Sox 10嵌合体构建体， 评估SoxE介导的神经嵴特化如何以及何时发生。此外，SOX 9和 SOX 10分别是Campomelic发育不良和Waardenburg综合征的病因。证候 存在非常不同的颅面表型，这些表型反映了S 0X 9/S 0X 10特定缺陷， 神经嵴特化这项研究的工作将导致新的SoxE转录靶点的鉴定， 确定SoxE因子何时开始促进神经嵴特化，并确定特定患者 Campomelic发育不良/Waardenburg综合征的变体引起疾病表型。总的来说，这项工作是 高的临床意义，并将提供进化的见解神经嵴的分子起源 多样化经营。我在本建议书指导阶段的主要目标是确定SoxE因素何时开始开始 促进神经嵴内的谱系特化，并确定有助于 SoxE家族亚功能化。我打算利用博士后的剩余时间， 实验技术和发展强大的计算分析。我会利用富有的学者 西北大学的环境，特别是NSF西蒙斯定量生物学中心的专业知识。 我的长期职业目标是建立一个独立的研究计划，使用多个模型系统， 研究以颅面表型为特征的综合征的细胞和分子起源。我计划 使用Sox转录因子（和相关综合征）作为我职业生涯的起点，但随后扩展了我的 通过与临床医生的合作，将研究兴趣扩展到其他基因家族。我的可衡量的经验， 各种模式生物将使我能够研究生物化学、分子、细胞和形态学方面的问题 通过利用每个模型系统的好处来研究发育障碍。

Project Summary/Abstract Neurocristopathies are a class of syndromes that are predominately characterized by malformations in the craniofacial complex. These defects are caused by aberrant development of the neural crest, a stem cell population unique to vertebrates. One distinctive feature of the neural crest is their ability to give rise to both ectomesenchymal (bone/cartilage) and non-ectomesenchymal (melanocytes and peripheral neurons/glia) derivatives. SoxE transcription factors play important roles in both the formation and the diversification of the neural crest. All three SoxE factors (Sox8, Sox9, and Sox10) function redundantly to promote neural crest formation. Interestingly, individual SoxE factors direct the differentiation of the neural crest into distinct lineages. Sox9 promotes chondrogenesis while Sox10 supports both the melanocyte and peripheral neuron/glial fates. An outstanding question is how these highly similar SoxE factors lead to neural crest specialization. This proposal utilizes omics-based approaches, gain and loss of function experiments, and Sox9-Sox10 chimera constructs to assess how and when SoxE-mediated neural crest specialization occurs. Furthermore, mutations in SOX9 and SOX10 are causative for Campomelic dysplasia and Waardenburg syndrome, respectively. The syndromes present with very different craniofacial phenotypes which are reflective of SOX9/SOX10 specific defects during neural crest specialization. Work from this study will lead to the identification of novel SoxE transcriptional targets, determine when SoxE factors begin to promote neural crest specialization, and determine how specific patient variants for Campomelic dysplasia/Waardenburg syndrome cause disease phenotypes. Overall, this work is of high clinical significance and will provide evolutionary insights into the molecular origins of neural crest diversification. My primary goal for the mentored phase of this proposal is to identify when SoxE factors begin to promote lineage specialization within the neural crest and determine the functional domains that contribute to SoxE family subfunctionalization. I plan to use my remaining time as a postdoctoral fellow to master new experimental techniques and develop robust computational analyses. I will capitalize on the rich academic environment of Northwestern University, especially the expertise in NSF-Simons Center for Quantitative Biology. My long-term career goal is to establish an independent research program that uses multiple model systems to investigate the cellular and molecular origins of syndromes characterized by craniofacial phenotypes. I plan to use Sox transcription factors (and associated syndromes) as a starting point in my career, but then extend my research interests to other gene families through collaboration with clinicians. My measurable experience with various model organisms will allow me to investigate biochemical, molecular, cellular, and morphological aspects of developmental disorders by exploiting the benefits of each model system.