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: 10843333
• 负责人: Erica Hutchins
• 金额: $ 3.89万
• 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/10843333
• 关键词: Affect; Binding; Biochemistry; Bioinformatics; Biological Assay; Cadherins; Cartilage; Cell Adhesion; Cell Adhesion Molecules; Cell-Cell Adhesion; Central Nervous System; 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; 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; Pathway interactions; Phase; Play; Population; Post-Transcriptional Regulation; Protein Secretion; Proteins; RNA; RNA-Binding Proteins; Regulation; Reporter; Research; Role; Site; Skeleton; Snails; 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; posttranscriptional; public health relevance; receptor; sensor; spatiotemporal; stem cell population

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.

项目概要 神经嵴 (NC) 是起源于正在形成的中枢神经的干细胞群 系统。 NC 细胞通过经历时空调节的上皮细胞与神经上皮细胞分层 间充质转化 (EMT) 以头尾相连的协调波形式进行，最终从神经管中退出。 颅内 NC 细胞，出现在胚胎头部区域，是体内唯一具有 分化为颅面骨骼和软骨的能力，是面部发育不可缺少的； 影响 NC 发育的突变会导致影响颅面部的多种疾病和畸形 结构（例如 Treacher Collins 综合征、腭裂等）。因此，对法规的全面了解 颅面 NC EMT 的评估对于确定颅面异常的病因至关重要。 迄今为止，研究的重点是解开神经元控制颅脑 NC 感应的早期事件。 板边界和神经管分层的机制。然而，人们对此知之甚少 控制 NC EMT 时间和从神经管退出的监管变化。我的初步研究 证明 Wnt 通路拮抗剂 Draxin 在控制 NC 时间上发挥着重要作用 EMT，其扰动会对颅脑 NC 迁移产生负面影响。 Draxin 的这个角色是 特别有趣的是，Wnt 信号通路已被证明是一个主要驱动因素 数控开发。本提案的目的是研究 Draxin 影响的分子机制 颅脑 NC EMT，重点关注其在 Wnt 信号传导中的作用。为此，本提案的具体目标旨在 将雏鸡胚胎学与最先进的成像和生物化学相结合： 1) 表征颅脑 NC EMT 中 Draxin 和 Wnt 信号传导的相互作用； 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；和 4）确定Draxin在细胞外基质蛋白调节中的作用。 该提案的结果将显着增强我们对颅脑 NC 调控的理解 EMT 和迁移，为治疗中的转化研究应用提供新的科学途径 颅面缺陷。