Characterization of the roles and regulation of Draxin in cranial neural crest

Draxin 在颅神经嵴中的作用和调节的表征

• 批准号: 10632334
• 负责人: Erica Hutchins
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10632334
• 关键词: Affect; Binding; Biochemistry; Bioinformatics; Biological Assay; Cartilage; Cell Adhesion; Cell Adhesion Molecules; Cell-Cell Adhesion; Cephalic; ChIP-seq; Chick; Cleft Palate; Co-Immunoprecipitations; Craniofacial Abnormalities; Data; Defect; Development; DiGeorge Syndrome; Disease; Down-Regulation; E-Cadherin; Embryo; Embryology; Etiology; Event; Extracellular Matrix Proteins; Face; Fluorescence Resonance Energy Transfer; Gelatinase B; Gene Expression; Genetic Transcription; Genomic Segment; Goals; Head; Image; Immunoprecipitation; In Situ Hybridization; Integrins; Laminin; Lead; Ligation; Light; Maintenance; Mandibulofacial Dysostosis; Mediating; Mentors; Messenger RNA; Microscopy; Molecular; Mutate; Mutation; N-Cadherin; Names; Neural Crest; Neural Crest Cell; Neural tube; Neuraxis; Pathway interactions; Phase; Play; Population; Post-Transcriptional Regulation; Proteins; RNA; RNA-Binding Proteins; Regulation; Reporter; Research; Role; Site; Skeleton; Tail; Techniques; Time; Translational Research; Untranslated Regions; Up-Regulation; WNT Signaling Pathway; antagonist; beta catenin; craniofacial; craniofacial structure; epithelial to mesenchymal transition; experimental study; in vivo; knock-down; laminin alpha5; mRNA Expression; malformation; migration; neural plate; neuroepithelium; overexpression; public health relevance; receptor; sensor; spatiotemporal; stem cell population; time use

PROJECT SUMMARY The neural crest (NC) is a stem cell population that originates within the forming central nervous system. NC cells delaminate from the neuroepithelium by undergoing a spatiotemporally regulated epithelial-to- mesenchymal transition (EMT) that proceeds in a coordinated wave head-to-tail to exit from the neural tube. Cranial NC cells, which arise in the head region of the embryo and are the only NC population in vivo with the ability to differentiate into craniofacial skeleton and cartilage, are indispensable for the development of the face; mutations affecting NC development result in numerous diseases and malformations affecting the craniofacial structures (e.g. Treacher Collins syndrome, cleft palate, etc.). Thus, a thorough understanding of the regulation of cranial NC EMT is essential to identify the etiology of craniofacial abnormalities. To date, research has focused on unraveling early events governing cranial NC induction at the neural plate border and the mechanism of delamination from the neural tube. However, little is known about the regulatory changes governing the timing of NC EMT and exit from the neural tube. My preliminary studies demonstrate that a Wnt pathway antagonist, Draxin, plays an important role in controlling the timing of NC EMT, perturbations of which have negative consequences for cranial NC migration. This role for Draxin is particularly interesting in light of the fact that the Wnt signaling pathway has been shown to be a major driver of NC development. The goal of this Proposal is to investigate the molecular mechanism by which Draxin affects cranial NC EMT, with focus on its role in Wnt signaling. To this end, the Specific Aims of this Proposal seek to combine chick embryology with state-of-the-art imaging and biochemistry to: 1) Characterize the interaction of Draxin and Wnt signaling in cranial NC EMT; 2) Identify the role of Draxin in the regulation of cell adhesion proteins; 3) Characterize the post-transcriptional regulation of Draxin; and 4) Identify the role of Draxin in the regulation of extracellular matrix proteins. The results of this Proposal will significantly enhance our understanding of the regulation of cranial NC EMT and migration, providing new scientific avenues for translational research applications in the treatment of craniofacial defects.

项目摘要 神经嵴（NC）是起源于形成中枢神经系统的干细胞群。 系统NC细胞通过经历时空调节的上皮细胞-神经上皮细胞-神经细胞- 间充质转化（EMT），其以协调的波从头到尾进行以从神经管退出。 颅部NC细胞，其产生于胚胎的头部区域，并且是体内唯一的NC群体， 能够分化成颅面骨骼和软骨，是面部发育不可缺少的; 影响NC发育的突变导致许多影响颅面的疾病和畸形 结构（例如Treacher柯林斯综合征、腭裂等）。因此，对法规的透彻理解 对颅面异常的病因诊断有重要意义。 到目前为止，研究集中在解开早期事件的支配颅NC感应在神经 板边界和神经管脱层的机制。然而，人们对此知之甚少。 调控NC EMT和退出神经管的时间的调节变化。我的初步研究 表明Wnt通路拮抗剂Draxin在控制NC的时间中起重要作用， EMT，其扰动对颅NC迁移具有负面影响。Draxin的角色是 特别有趣的是，Wnt信号通路已被证明是一个主要的驱动因素， NC开发该提案的目标是研究Draxin影响的分子机制 颅NC EMT，重点是其在Wnt信号传导中的作用。为此，本提案的具体目标是： 联合收割机将鸡胚胎学与最先进的成像和生物化学技术相结合，以： 1)表征Draxin和Wnt信号在颅NC EMT中的相互作用; 2)确定Draxin在细胞粘附蛋白调节中的作用; 3)表征Draxin的转录后调控;以及 4)确定Draxin在细胞外基质蛋白调节中的作用。 这项建议的结果将大大提高我们对颅NC调节的理解 EMT和迁移，为转化研究在治疗中的应用提供了新的科学途径， 颅面缺损