Genetic Analysis of Inner Ear Development in tropicalis

描述(由申请者提供)：为了促进我们对耳朵发育以及潜在的分子和遗传相互作用的了解，我们正在对最近引入的遗传模式动物热带非洲爪哇进行正向遗传筛查。这项初步研究揭示了几个与耳朵形态、耳石形成和平衡/游泳行为有关的基因座。重要的是，热带管圆线虫耳部形态发生的主要事件可以在活体胚胎中观察到，这极大地有助于筛查遗传缺陷。之前在耳朵发育方面的工作已经证明，从人类到青蛙，潜在的分子机制都被很好地保守，这使得遗传上服从和卵生的热带X.tropicis成为一种有吸引力的模式动物，用来研究听力和平衡异常的原因以及潜在的分子和遗传相互作用。之前已经在斑马鱼和老鼠身上进行了内耳突变的筛选，我们希望在非洲爪哇中发现重叠和不同的突变。在这项建议中，我们将识别和定位影响耳朵的突变，并将它们与先前已知的候选基因联系起来，或者将它们识别为参与耳朵发育的新基因座。我们将描述突变的表型，集中在新的基因座上。这将使热带非洲爪哇成为了解耳朵发育和疾病的有效新系统。正如计划公告中所描述的，人类内耳的形成是复杂的，对正常发育和发育障碍都知之甚少。对内耳发育的理解将得益于对热带非洲爪哇等模式生物的研究，在这些模式生物中，突变表型可以用来理解正常发育的潜在机制。

DESCRIPTION (provided by applicant): To advance our understanding of ear development and the underlying molecular and genetic interactions, we are undertaking a forward genetic screen in the amphibian Xenopus tropicalis, a recently introduced genetic model animal. This pilot study reveals several loci involved in ear morphology, otolith formation, and balancing/swimming behavior. Importantly, the major events of X. tropicalis ear morphogenesis can be observed externally in the living embryos, greatly aiding screens for genetic defects. Previous work in ear development has demonstrated that underlying molecular mechanisms are well conserved from human to frog, making genetically amenable and oviparous X. tropicalis an attractive model animal in which to study the causes of hearing and balance anomalies as well as underlying molecular and genetic interactions. Previous screens for inner ear mutants have been done in zebrafish and mouse, and we expect to find both overlapping and different mutations in Xenopus. In this proposal we shall identify and map mutations affecting the ear, and link them to previously known candidate genes, or identify them as new loci involved in ear development. We shall characterize the mutant phenotypes, concentrating on the novel loci. This will establish Xenopus tropicalis as an effective new system to understand ear development and disorders. As described in the Program Announcement, the formation of the human inner ear is complex, and both the normal development and developmental disorders are poorly understood. The understanding of inner ear development will benefit from studies in model organisms such as Xenopus tropicalis, where mutant phenotypes can be used to understand the underlying mechanisms for normal development.