The Role of SoxE Transcription Factors in Neural Crest Cell Specialization

SoxE 转录因子在神经嵴细胞特化中的作用

• 批准号: 10662767
• 负责人: Elizabeth (Betsy) Schock
• 金额: $ 9.7万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662767
• 关键词: ATAC-seq; Biochemical; Biological Models; Biology; Brightfield Microscopy; Cartilage; Cell Culture Techniques; Cells; ChIP-seq; Chick; Chimera organism; Chimeric Proteins; Chondrogenesis; Chromatin; Collaborations; Computer Analysis; Congenital Abnormality; Coupled; Craniofacial Abnormalities; DNA Binding Domain; Data Analyses; Defect; Development; Disease; Dominant-Negative Mutation; Embryo; Environment; Etiology; Face; Family; Future; Gene Activation; Gene Family; Genes; Genetic Transcription; Genome; Genotype; Global Change; Goals; Heterogeneity; Human; Individual; Lead; Link; Measurable; Mediating; Mentors; Molecular; Morphology; Mutation; Neural Crest; Neural Crest Cell; Neuroglia; Neurons; Patients; Peripheral; Peripheral Nervous System; Phase; Phenotype; Pigments; Play; Population; Postdoctoral Fellow; Proteins; Research; Role; SOX8 gene; Specificity; Stains; Syndrome; Tadpoles; Techniques; Tertiary Protein Structure; Time; Universities; Variant; Vertebrates; Waardenburg syndrome; Work; Xenopus; Xenopus laevis; bone; campomelic dysplasia; career; cell type; clinically significant; craniofacial; craniofacial complex; craniofacial development; craniofacial disorder; developmental disease; directed differentiation; disease phenotype; experience; experimental study; gain of function; insight; interest; loss of function; malformation; melanocyte; migration; model organism; neurodevelopment; novel; programs; screening; stem cell population; transcription factor; transcriptome sequencing; work-study

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.

项目摘要/摘要 神经管疾病是一类以脑部畸形为主要特征的综合征。 头面部复合体。这些缺陷是由干细胞神经脊的异常发育引起的。 脊椎动物特有的种群。神经脊的一个显著特征是，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) 衍生品。SOXE转录因子在细胞的形成和分化中起着重要的作用 神经顶峰。所有三个SoxE因子(Sox8、Sox9和Sox10)都冗余地促进神经波峰 队形。有趣的是，个体SoxE因子引导神经脊分化成不同的谱系。 Sox9促进软骨形成，而Sox10支持黑素细胞和外周神经元/神经胶质细胞的命运。一个 悬而未决的问题是，这些高度相似的SoxE因素是如何导致神经脊特化的。这项建议 利用基于组学的方法、功能得失实验和Sox9-Sox10嵌合体构建 评估SoxE介导的神经脊特化发生的方式和时间。此外，SOX9和SOX9的突变 SOX10分别是驼核发育不良和瓦登堡综合征的致病因素。证候 表现出非常不同的头面部表型，反映了SOX9/SOX10特定的缺陷 神经脊的专门化。这项研究的工作将导致识别新的SoxE转录靶点， 确定SoxE因素何时开始促进神经脊特化，并确定患者的具体情况 驼核发育不良/瓦登堡综合征的变异会导致疾病表型。总体而言，这项工作是 具有很高的临床意义，并将为神经脊的分子起源提供进化见解 多元化。我在此提案的指导阶段的主要目标是确定SoxE因素何时开始 促进神经脊内的谱系专门化，并确定有助于 SOXE家族的子功能化。我计划利用我博士后的剩余时间来掌握新的 实验技术和开发可靠的计算分析。我要利用这位富有的学者 西北大学的环境，特别是NSF-Simons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项目，使用多种模型系统来 探讨以颅面部表型为特征的综合征的细胞和分子起源。我计划这样做 使用SOX转录因子(和相关综合征)作为我职业生涯的起点，但随后扩展我的 通过与临床医生的合作，吸引其他基因家族的研究兴趣。我的可衡量的经验是 各种模型生物将使我能够研究生化、分子、细胞和形态方面的问题。 通过利用每个模型系统的好处来预防发育障碍。

项目成果

Shared features of blastula and neural crest stem cells evolved at the base of vertebrates.

囊胚和神经嵴干细胞的共同特征是在脊椎动物的基础上进化而来的。

• DOI: 10.1101/2023.12.21.572714
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: York,JoshuaR;Rao,Anjali;Huber,PaulB;Schock,ElizabethN;Montequin,Andrew;Rigney,Sara;LaBonne,Carole
• 通讯作者: LaBonne,Carole