Characterization and cloning of X. tropicalis Craniofacial Mutants

热带 X. 热带菌颅面突变体的表征和克隆

• 批准号: 7932553
• 负责人: Mustafa K Khokha
• 金额: $ 20万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932553
• 关键词: Affect; Biological Models; Branchial arch structure; Candidate Disease Gene; Cell Death; Cell division; Child; Childhood; Cloning; Congenital Abnormality; Data; Defect; Development; Disease; Embryo; Embryonic Development; Endothelin; Evolution; Exhibits; Face; Funding; Future; Genes; Genetic; Genetic Models; Genetic Screening; Genomics; Glean; Goals; Grant; Head; Head and neck structure; Health; Human; Hybrids; Infant; Infant Mortality; Inheritance Patterns; Inherited; Jaw; Lead; Learning; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Mutate; Mutation; Neural Crest; Neural Crest Cell; Oligonucleotides; Pathway interactions; Pattern; Phenocopy; Phenotype; Proteins; Rana; Recombinants; Research Personnel; Series; Severity of illness; Signal Transduction; Staging; Structure; System; Testing; Tissues; Transcript; Ursidae Family; Xenopus; Yaws; base; comparative; cost effective; craniofacial; gene function; genetic analysis; human disease; improved; insight; knock-down; malformation; migration; mutant; novel; positional cloning; programs; research study; skeletal

DESCRIPTION (provided by applicant): Craniofacial malformations are among the most common birth defects in children and lead to substantial morbidity and mortality for these infants. Despite the severity of the illness, little is known about the molecular mechanisms that are necessary for correct formation of facial structures. In this proposal, we will investigate craniofacial development in an emerging model system, Xenopus tropicalis. During a recent forward genetic screen, we identified two mutants, jaws and jawbreaker, that exhibit a specific embryonic defect in the development of craniofacial structures. These mutants show a simple Mendelian inheritance pattern suggestive of a single recessive mutant locus. Outside of the craniofacial defect, the remainder of the embryo appears wildtype. It is the goal of this proposal to characterize these two mutants and identify where and when during development craniofacial patterning begins to fail. In a second aim, we will attempt to identify the mutant locus which will greatly improve our understanding of the molecular patterning defect. Because our understanding of craniofacial morphogenesis remains superficial, characterizing these mutants has the potential of substantially improving our understanding of craniofacial development and malformations. In addition, this will represent one of the very first attempts to clone a mutant identified in a forward genetic screen in X. tropicalis. Successful completion of these goals will greatly support future genetic screens in this emerging model system. Birth defects of the head and neck are a common cause of serious illness in infants. Yet, our scientific understanding of how these structures form during embryonic development remains superficial. We propose a series of experiments to analyze two frog mutants that have abnormal jaw structure. A better understanding of these frog mutants can then be used as a model to understand birth defects of the head and neck in humans.

描述（由申请人提供）：颅面畸形是儿童最常见的出生缺陷之一，导致这些婴儿的发病率和死亡率很高。尽管这种疾病很严重，但人们对正确形成面部结构所必需的分子机制知之甚少。在本提案中，我们将研究新兴模型系统热带爪蟾的颅面发育。在最近的一次正向遗传筛选中，我们发现了两种突变体：颌骨和颌骨破坏者，它们在颅面结构的发育中表现出特定的胚胎缺陷。这些突变体显示出简单的孟德尔遗传模式，暗示单个隐性突变位点。除了颅面缺陷之外，胚胎的其余部分表现为野生型。该提案的目标是描述这两种突变体的特征，并确定在发育过程中颅面图案开始失效的位置和时间。第二个目标是，我们将尝试识别突变位点，这将极大地提高我们对分子图案缺陷的理解。由于我们对颅面形态发生的理解仍然很肤浅，因此表征这些突变体有可能大大提高我们对颅面发育和畸形的理解。此外，这将是克隆在热带角线虫中通过正向遗传筛选鉴定出的突变体的首次尝试之一。这些目标的成功完成将极大地支持这一新兴模型系统中未来的基因筛选。 头部和颈部的出生缺陷是婴儿严重疾病的常见原因。然而，我们对胚胎发育过程中这些结构如何形成的科学理解仍然很肤浅。我们提出了一系列实验来分析两种具有异常颌骨结构的青蛙突变体。对这些青蛙突变体的更好了解可以用作了解人类头部和颈部出生缺陷的模型。