Characterization and cloning of X. tropicalis Craniofacial Mutants

描述（由申请人提供）：颅面畸形是儿童中最常见的出生缺陷之一，并导致这些婴儿的大量发病率和死亡率。尽管疾病的严重性，很少有人知道的分子机制，是必要的面部结构的正确形成。在这个建议中，我们将调查颅面发展的一个新兴的模型系统，热带爪蟾。在最近的遗传筛查中，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。这些突变体显示出一个简单的孟德尔遗传模式，提示一个单一的隐性突变位点。在颅面缺陷之外，胚胎的其余部分表现为野生型。这是本提案的目标，这两个突变体的特点，并确定在发展过程中颅面图案开始失败的位置和时间。在第二个目标中，我们将尝试鉴定突变位点，这将大大提高我们对分子模式缺陷的理解。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，这将代表克隆在X中的正向遗传筛选中鉴定的突变体的最初尝试之一。热带植物这些目标的成功完成将极大地支持未来在这个新兴的模型系统的遗传筛选。 头部和颈部的出生缺陷是婴儿严重疾病的常见原因。然而，我们对这些结构在胚胎发育过程中如何形成的科学理解仍然很肤浅。我们提出了一系列的实验来分析两个青蛙突变，有异常的下巴结构。更好地了解这些青蛙突变体，然后可以作为一个模型来了解人类头部和颈部的出生缺陷。

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.