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: 10653270
• 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/10653270
• 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.

项目摘要 神经rest（NC）是一种干细胞种群，起源于中枢神经内 系统。 NC细胞通过经过时空调节的上皮到 - 间充质转变（EMT）以协调的波从头到尾进行，从神经管中退出。 颅NC细胞，在胚胎的头部区域出现，是体内唯一的NC种群 能够区分颅面骨骼和软骨，对于面部的发展是必不可少的。 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，背叛者柯林斯综合症，c裂等）。因此，对法规的透彻理解 颅内NC EMT的识别对于识别颅面异常的病因至关重要。 迄今为止，研究的重点是揭示有关神经颅NC诱导的早期事件 板边框和神经管的分层机制。但是，关于 管理NC EMT的时间并从神经管中退出的调节变化。我的初步研究 证明Wnt途径拮抗剂Draxin在控制NC的时机中起着重要作用 EMT，其扰动对颅NC迁移产生负面影响。 Draxin的这个角色是 鉴于Wnt信号通路已被证明是 NC开发。该提案的目的是研究德拉克斯影响的分子机制 颅NC EMT，重点是其在Wnt信号传导中的作用。为此，该提案的具体目标寻求 将雏鸡的胚胎学与最先进的成像和生物化学相结合： 1）表征颅NC EMT中Draxin和Wnt信号传导的相互作用； 2）确定draxin在调节细胞粘附蛋白中的作用； 3）表征Draxin的转录后调节；和 4）确定draxin在调节细胞外基质蛋白中的作用。 该提案的结果将大大增强我们对颅NC调节的理解 EMT和移民，为翻译研究应用提供了新的科学途径 颅面缺陷。