The Zebrafish Model of Microphthalmia

描述（由申请人提供）：组织生长的调控对于理解脊椎动物（包括人类）的胚胎发生至关重要。它也有巨大的医学意义。与正常组织生长的偏离会导致胚胎发育过程中严重的图案缺陷，并在成熟的生物体中导致癌症。细胞增殖的异常模式在人类中产生了许多发育性眼睛疾病。其中之一是小眼症，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，我们选择使用斑马鱼作为动物模型。斑马鱼的基因筛选发现了许多导致眼睛变小的突变。最严重的小眼表型之一是由视线外（out）位点的缺陷引起的。该项目的目标是确定out基因的分子性质，并在细胞水平上发展对其功能的理解。一旦这个基因的分子身份被确定，我们将通过筛选患病个体的DNA样本来研究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已经非常有效，导致在几个基因中识别引起小眼的突变，包括rx， six6和sox2。这个项目是在更大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。这一策略很可能对了解人类小眼症及其更严重的形式无眼症的遗传原因作出重大贡献。我们将使用动物模型，斑马鱼，来识别导致小眼症的基因，这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没有眼睛。这些研究将深入了解这种使人衰弱的疾病的遗传基础，这种疾病每5000名儿童中就有1名受到影响。

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.