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 神经科学病是一类综合症，主要以畸形为特征 颅面复合物。这些缺陷是由神经rest的异常发育引起的，一种干细胞 脊椎动物独有的种群。神经波峰的一个独特特征是它们产生两者的能力 外质（骨/软骨）和非直骨大质（黑色素细胞和周围神经元/神经胶质） 衍生物。袜子转录因子在形成和多样化中都起着重要作用 神经波峰。所有三个SOXE因子（Sox8，Sox9和Sox10）都起作用以促进神经rest 形成。有趣的是，单个袜子因素将神经rest的分化指向不同的谱系。 SOX9促进软骨发生，而Sox10支持黑色素细胞和周围神经元/神经胶质命运。一个 杰出的问题是这些高度相似的Soxe因素如何导致神经Crest专业化。这个建议 利用基于OMICS的方法，功能实验的增益和丧失，Sox9-Sox10 Chimera构建到 评估Soxe介导的神经Crest专业化的方法和何时。此外，Sox9和 Sox10分别对campomelic发育不良和Waardenburg综合征是病因。综合征 存在非常不同的颅面表型，这些表型反映了Sox9/Sox10在 神经波峰专业。这项研究的工作将导致识别新型的Soxe转录目标， 确定索克斯因素何时开始促进神经Crest专业化，并确定特定患者如何 露营性发育不全/瓦登堡综合征的变体引起疾病表型。总的来说，这项工作是 高临床意义，并将为神经rest的分子起源提供进化见解 多样化。我对该提案的指导阶段的主要目标是确定何时开始袜子因素 促进神经波峰内的血统专业化，并确定有助于 索斯家族的亚功能化。我计划利用我作为博士后研究员的剩余时间来掌握新的 实验技术并开发可靠的计算分析。我将利用富裕的学术 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计划，该计划使用多个模型系统来 研究以颅面表型为特征的综合征的细胞和分子起源。我打算 使用Sox转录因子（及相关综合征）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来研究其他基因家族。我的可衡量经验 各种模型生物将使我能够研究生化，分子，细胞和形态学方面 通过利用每个模型系统的益处来实现发育障碍。

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