Function of the Six and Eya Genes in Retinal Development

Six 和 Eya 基因在视网膜发育中的功能

• 批准号: 8265287
• 负责人: Justin P Kumar
• 金额: $ 36.96万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265287
• 关键词: Address; Adopted; Anophthalmos; Apoptosis; Bilateral; Binding Sites; Biochemical; Bioinformatics; Biological Assay; Biological Models; Branchio-Oto-Renal Syndrome; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Chimeric Proteins; Complex; Confocal Microscopy; Consensus; DNA Microarray Chip; Data; Defect; Development; Drosophila eye; Drosophila genus; Drosophila melanogaster; Experimental Designs; Eye; Eye Development; Family; Flow Cytometry; Gap Junctions; Gene Expression; Gene Expression Regulation; Gene Family; Gene Targeting; Genes; Genomics; Goals; Growth; Holoprosencephaly; Homeobox; Human; Insecta; Knowledge; Lead; Lesion; Link; Malignant Neoplasms; Mammals; Methods; Molecular; Molecular Genetics; Monitor; Mutation; Myotonic Dystrophy; Patients; Pattern; Phenotype; Play; Primordium; Process; Proliferating; Protein Family; Protein Tyrosine Phosphatase; Proteins; Regulation; Repressor Proteins; Retina; Retinal; Retinal Defect; Retinal Diseases; Role; Stereotyping; System; Testing; Tissues; Transcription Coactivator; Transcription Repressor/Corepressor; VP 16; Visual; Work; Yeasts; compound eye; congenital cataract; eye primordia; fly; in vivo; insight; interest; loss of function; loss of function mutation; member; mouse model; mutant; prevent; protein function; retinogenesis; transcription factor; tumorigenesis

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.

项目摘要：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动，其中包括 Pax、Six、Eya 和 Dach 基因家族的成员。该提案特别令人感兴趣的是角色 六蛋白和 Eya 蛋白在视网膜中发挥作用。这些基因家族的功能非常重要 因为某些基因的突变可能导致前脑无裂畸形、双侧无眼症、先天性畸形 白内障以及非视网膜缺陷，例如强直性肌营养不良和鳃耳肾综合征。 此外，这些基因还与肿瘤发生和多种癌症有关。六种蛋白质 作为含有转录因子的同源盒，而 Eya 蛋白则作为转录辅助蛋白 激活剂和蛋白质酪氨酸磷酸酶。这些蛋白质家族通过形成 Six-Eya 进行合作 异二聚体被认为是下游靶基因的强激活剂。活动内容 这些异二聚体的研究至关重要，因为功能丧失突变可能导致人类视网膜缺陷 患者和小鼠模型系统以及彻底消除果蝇的复眼， 黑腹果蝇。 Six 和 Eya 基因损伤与视网膜疾病的关联 昆虫和哺乳动物系统为我们提供了一个令人兴奋的机会来进一步探索 这些因素在视网膜发生中发挥作用。果蝇发育中的眼睛已成为首要模型 用于研究控制组织决定的遗传和分子机制的系统。这 优点包括已得到充分描述的定型发展模式、大量的 已知眼睛规格基因和大量可用突变菌株的实验数据 分子/细胞标记。在果蝇中，眼睛缺失是 Eya 家族的唯一成员，而正弦 oculis、optix 和 DSix4 代表 Six 基因家族。尽管已经做出了巨大努力 在了解这些基因在发育中所起的作用的基础上，有大量的 仍未得到解答的重要问题。拟议工作的目标是解决这些问题 提出问题并提供答案，以进一步了解 Six 和 Eya 基因所扮演的角色 在视网膜测定中。在本提案中，我们将尝试确定 (1) optix 在以下方面所扮演的角色： 眼睛发育正常； (2)眼正弦与缺如眼在连接视网膜中所起的作用 细胞周期和组织生长的规范； (3) Sine 转录靶标的身份 眼睛规范期间的眼及其对其调节的影响。为了解决 这些问题我们将创造性地结合遗传、分子和生化方法 使用基因组和生物信息方法来研究这些问题。