Function of the Six and Eya Genes in Retinal Development

项目概述：包括眼睛在内的许多哺乳动物组织的早期发育 部分取决于进化上保守的调节回路的活性，包括 Pax、Six、Eya和Dach基因家族的成员。这项建议特别令人感兴趣的是， Six和Eya蛋白在视网膜中的作用。这些基因家族的功能非常重要 由于选择基因的突变可导致前脑无裂畸形、双侧无眼畸形、先天性 白内障以及非视网膜缺陷如肌强直性营养不良和鳃耳肾综合征。 此外，这些基因也与肿瘤发生和许多癌症有关。六种蛋白质 Eya蛋白作为转录辅因子发挥功能， 活化剂和蛋白酪氨酸磷酸酶。这些蛋白质家族通过形成Six-Eya 异二聚体被认为是下游靶基因的强激活剂。活动 这些异源二聚体的突变是至关重要的，因为功能丧失突变可导致人类视网膜缺陷。 患者和小鼠模型系统以及完全消除果蝇复眼， 果蝇Six和Eya基因病变与视网膜病变的相关性 昆虫和哺乳动物系统为我们提供了一个令人兴奋的机会，以进一步探索的作用， 这些因素在视网膜发生中起作用。果蝇发育中的眼睛已经成为 用于研究支配组织决定的遗传和分子机制的系统。的 优势包括已经被很好地描述的定型发展模式， 关于已知眼睛特化基因和大量可用突变株的实验数据， 分子/细胞标记物。在果蝇中，Eya家族只有眼睛缺失，而Sine家族只有眼睛缺失。 oculis、optix和DSix 4代表Six基因家族。尽管已经做出了重大努力， 为了理解这些基因在发育中所起的作用， 仍然没有答案的重要问题。拟议工作的目标是解决这些问题 问题，并提供答案，将进一步我们的理解所发挥的作用，六和Eya基因 在视网膜的决定。在本提案中，我们将试图确定（1）optix在以下方面的作用： 正常眼的发育;（2）单眼与眼缺如在视网膜连接中的作用 Sine的转录靶点的确定 在眼睛规格和它对他们的调节的影响。为了解决 这些问题，我们将使用创造性的混合遗传，分子和生物化学的方法沿着 用基因组学和生物信息学的方法来研究这些问题。

Project Summary: The early development of a number of mammalian tissues including the eye depends in part upon the activity of an evolutionarily conserved regulatory circuit that includes members of the Pax, Six, Eya and Dach gene families. Of particular interest to this proposal is the role that the Six and Eya proteins play in the retina. The function of these gene families are highly significant as mutations in select genes can lead to holoprosencephaly, bilateral anophthalmia, congenital cataracts as well as non-retinal defects such as myotonic dystrophy and branchio-oto-renal syndrome. Furthermore, these genes are also implicated in tumorigenesis and numerous cancers. Six proteins serve as homeobox containing transcription factors while Eya proteins function as transcriptional co- activators and as protein tyrosine phosphatases. These protein families cooperate by forming Six-Eya heterodimers that are thought to function as strong activators of downstream target genes. The activity of these heterodimers is crucial as loss-of-function mutations can lead to retinal defects in human patients and mouse model systems as well as total elimination of the compound eyes of the fruit fly, Drosophila melanogaster. The association of Six and Eya gene lesions with retinal disorders in both insect and mammalian systems provides us with an exciting opportunity to further explore the roles that these factors play in retinogenesis. The developing eye of the fruit fly has become a premier model system for studying the genetic and molecular mechanisms that govern tissue determination. The advantages include a stereotyped mode of development that has been well described, a large body of experimental data on known eye specification genes and a vast array of available mutant strains and molecular/cellular markers. In Drosophila, eyes absent is the sole member of the Eya family while sine oculis, optix and DSix4 represent the Six gene family. Despite the significant efforts that have been placed on understanding the roles that these genes play in development there are a large number of important questions that still remain unanswered. The goals of the proposed work are to address these questions and provide answers that will further our understanding of role played by Six and Eya genes in retinal determination. In this proposal we will attempt to determine (1) the role that optix plays in normal eye development; (2) the part that sine oculis and eyes absent plays in linking retinal specification to the cell cycle and tissue growth; and (3) the identity of the transcriptional targets of Sine Oculis during eye specification and the influence that it has on their regulation. In order to address these issues we will use a creative mixture of genetic, molecular and biochemical approaches along with genomic and bioinformatic methods to investigate these issues.