Characterization of craniofacial development in a zebrafish mutant lacking all cr

缺乏所有 cr 的斑马鱼突变体的颅面发育特征

基本信息

批准号：
8250513
负责人：
TRACIE L FERREIRA
金额：
$ 4.54万
依托单位：
UNIVERSITY OF MASSACHUSETTS DARTMOUTH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250513
关键词：
Adopted Apoptosis Biological Process Boston Brain Cartilage Cell Death Cell Transplantation Cells Cephalic Cerebral Ventricles Congenital Abnormality Coupled Data Defect Development DiGeorge Syndrome Dorsal Embryo Employee Strikes Endoderm Ethylnitrosourea Event Face Fetus Foundations Future Gene Mutation Generations Genes Genetic Genetic Identity Genetic Screening Goals Growth Head Health Histology Human Imagery In Situ In Situ Hybridization Inherited Injection of therapeutic agent Knowledge Link Mesenchyme Messenger RNA Molecular Molecular Analysis Mutagenesis Mutate Mutation Nature Neural Crest Cell Neural Tube Closure Neural Tube Defects Neural tube Newborn Infant Partner in relationship Pathogenesis Pathology Pathway interactions Pattern Pediatric Hospitals Peripheral Nervous System Phenocopy Pigments Population Positioning Attribute Regulation Rhodamine Scientist Signal Pathway Signal Transduction Signaling Molecule Skeleton Specific qualifier value Staging Structure Study models Syndrome TdT-Mediated dUTP Nick End Labeling Assay Teratogens Time Work Zebrafish base blastomere structure cartilage cell craniofacial cranium design early experience genetic manipulation in vivo insight malformation member migration mutant novel orofacial positional cloning prevent progenitor research study smoothened signaling pathway therapeutic development therapy development

项目摘要

DESCRIPTION (provided by applicant): Neural tube and orofacial defects are common congenital malformations in humans. Craniofacial birth defects strike an average of 1 in 750 newborns and they are for the most part multifactorial in their pathogenesis, having both genetic and environmental components in their development. Neural Crest cells (NCCs) are a pluripotent cell population that originate in the dorsal neurectoderm to form the facial skeleton and most of the skull. Proper migration of NCCs from the neurectoderm is essential for correct patterning of the craniofacial structures. This migration is dependent on numerous cell signaling pathways which are vulnerable to environmental insults as well as inherited genetic defects. Understanding the temporal and spatial requirements of distinct signaling networks will allow for the development of therapies for specific craniofacial defects. Our approach uses the zebrafish which is amenable to numerous genetic manipulations and is genetically similar to higher mammalian species. In this study we will use a novel craniofacial mutant generated in a large scale ENU mutagenesis screen designed to identify craniofacial mutants. This mutant has neural tube defects and lacks all craniofacial cartilages, a novel defect not isolated in previous ENU screens performed in zebrafish. This work will focus on the molecular and physical characterization of this ghost (gho) mutant and will identify the genetic locus mutated in the gho mutant. These studies will help fill a gap that exists in regards to the identity and timing of the molecular signals required for neural tube closure and the signals required by neural crest cells to adopt specific fates. Our efforts, in addition to the work done in other labs, will ultimately allow for the development of therapeutics for specific early neural tube and craniofacial defects. PUBLIC HEALTH RELEVANCE: Neural tube and orofacial defects are common congenital malformations in humans, striking an average of 1 in 750 newborns. These defects can be caused by environmental teratogens and/or genetic defects. Using a zebrafish mutant that has severe craniofacial defects we will analyze its defective gene, work that will ultimately contribute to understanding part of the network of growth signals required for proper formation of the face, and help scientists develop pre-natal therapies to prevent such malformations.

描述（由申请人提供）：神经管和口面缺陷是人类常见的先天性畸形。颅面的先天缺陷平均袭击了750名新生儿中的1个，并且在其发病机理中大部分是多因素的，其发育中既有遗传和环境成分。神经rest细胞（NCC）是多能细胞群，起源于背膜胚层以形成面部骨骼和大多数头骨。 NCC从神经药物中的适当迁移对于正确对颅面结构的构图至关重要。这种迁移取决于众多易受环境侮辱以及遗传遗传缺陷的细胞信号通路。了解不同信号网络的时间和空间要求将允许开发特定颅面缺陷的疗法。我们的方法使用斑马鱼，该斑马鱼适合许多遗传操作，并且在遗传上与较高的哺乳动物物种相似。在这项研究中，我们将使用大规模的ENU诱变筛查中产生的新型颅面突变体，旨在鉴定颅面突变体。该突变体具有神经管缺陷，缺乏所有颅面软骨，这是一种在斑马鱼中进行的ENU筛查中未分离的新型缺陷。这项工作将集中于该幽灵（GHO）突变体的分子和物理表征，并将识别GHO突变体突变的遗传基因座。这些研究将有助于填补有关神经管闭合所需的分子信号的身份和时机存在的空白，以及神经Crest细胞采用特定命运所需的信号。除了在其他实验室所做的工作之外，我们的努力最终还将允许开发特定的早期神经管和颅面缺陷的治疗剂。公共卫生相关性：神经管和口面缺陷是人类常见的先天性畸形，平均在750名新生儿中平均有1个。这些缺陷可能是由环境破坏者和/或遗传缺陷引起的。使用具有严重颅面缺陷的斑马鱼突变体，我们将分析其缺陷的基因，最终将有助于理解面部适当形成所需的成长信号网络的一部分，并帮助科学家开发出产前疗法以防止这种畸形。