The Zebrafish Model of Microphthalmia

描述(由申请人提供)：组织生长的调节对于理解脊椎动物，包括人类胚胎发生至关重要。它还具有巨大的医学意义。偏离正常组织生长会在胚胎发育过程中导致严重的图案缺陷，并在成熟的生物体中导致癌症。细胞增殖的异常模式会在人类中产生许多发育障碍。其中之一是小眼炎，在最极端的情况下会导致完全没有眼睛。为了确定人类小眼症和无眼症的遗传原因，我们选择了一个动物模型--斑马鱼。斑马鱼的基因筛查发现了许多导致眼睛尺寸减小的突变。最严重的小眼睛表型之一是由视线外(Out)轨迹的缺陷引起的。该项目的目标是确定Out基因的分子性质，并在细胞水平上了解其功能。一旦知道了这个基因的分子特征，我们将通过筛选患病个体的DNA样本来调查它的缺陷是否与人类小眼症有关。类似的基于动物模型的方法非常有效，导致了几个导致小眼炎的基因的突变，包括RX、SIX6和SOX2。该项目是在更广泛的范围内使用斑马鱼突变体来确定眼睛生长障碍的遗传原因的第一步。从长远来看，斑马鱼很可能成为研究这类异常的候选基因的主要来源。这一策略可能会对理解人类小眼症及其更严重的形式--无眼症的遗传原因做出重大贡献。我们将使用斑马鱼的动物模型来识别导致小眼炎的基因，小眼炎是一种人类眼睛疾病，其特征是眼睛变小，在最极端的情况下是眼睛的缺失。这些研究将提供对这种每5000名儿童中就有一名儿童患有这种衰弱疾病的遗传基础的洞察。

DESCRIPTION (provided by applicant): The regulation of tissue growth is of paramount importance for the understanding of vertebrate, including human, embryogenesis. It has also a tremendous medical significance. Deviations from normal tissue growth lead to severe patterning defects during embryogenesis, and to cancer in the mature organism. Abnormal patterns of cell proliferation produce a number of developmental eye disorders in humans. One of them is microphthalmia, which in the most extreme cases leads to the complete absence of eyes. To identify the genetic causes of human microphthalmia and anophthalmia, we chose to use an animal model, the zebrafish. Genetic screens in zebrafish identified many mutations that result in a decreased eye size. One of the most severe small eye phenotypes is caused by defects of the out of sight (out) locus. The goal of this project is to identify the molecular nature of the out gene, and to develop an understanding of its function on the cellular level. Once the molecular identity of this gene is known, we will investigate whether its defects are responsible for human microophthalmia by screeing DNA samples from diseased individuals. Similar animal model-based approaches have been very productive, leading to the identification of microphthalmia-causing mutations in several genes, including rx, six6, and sox2. This project is the first step on the way to use zebrafish mutants on a broader scale to identify the genetic causes of eye growth disorders. In the long run, the zebrafish is likely to become a major source of candidate genes to study this class of abnormalities. This strategy is likely to make a major contribution to the understanding of the genetic causes of microphthalmia and its more severe form, anophthalmia, in humans. We will use animal model, the zebrafish, to identify genes responsible for microphthalmia, a human eye disorder characterized by a reduction of eye size, and in the most extreme the absence of eyes. These studies will provide insight into the genetic basis of this debilitating disorder that affects 1 in 5,000 children.