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.

项目总结 神经脊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到神经上皮细胞的脱层 间充质转化(EMT)在协调波中从头到尾从神经管退出。 颅骨NC细胞，出现在胚胎的头部区域，是体内唯一具有 分化为头面部骨骼和软骨的能力，对于面部的发育是不可或缺的； 影响NC发育的突变导致影响头面部的多种疾病和畸形 结构(例如，Treacher-Collins综合征、腭裂等)。因此，对该规定的透彻理解 头颅NC EMT对确定颅面畸形的病因具有重要意义。 到目前为止，研究的重点是在神经上解开控制颅脑NC诱导的早期事件 板边界和神经管分层的机制。然而，人们对此知之甚少 管理NC EMT和退出神经管的时机的监管变化。我的初步研究 证明Wnt通路拮抗剂Draxin在控制NC的时间上起着重要作用 EMT，其扰动对颅骨NC迁移具有负面影响。德拉新的这一角色是 尤其有趣的是，Wnt信号通路已被证明是 数控技术的发展。这项建议的目标是研究德拉新影响的分子机制。 颅脑NC EMT，重点介绍其在Wnt信号中的作用。为此目的，该提案的具体目标力求 将鸡胚学与最先进的成像和生物化学相结合，以： 1)研究DRAXIN和WNT信号在颅脑NC EMT中的相互作用； 2)明确Draxin在细胞黏附蛋白调控中的作用； 3)研究Draxin的转录后调控； 4)确定Draxin在细胞外基质蛋白调控中的作用。 这一建议的结果将极大地提高我们对颅脑NC调节的理解 EMT和迁移，为转化研究在治疗糖尿病中的应用提供了新的科学途径 头面部缺陷。