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: 7885124
• 负责人: Justin P Kumar
• 金额: $ 38.5万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885124
• 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; 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; 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; public health relevance; retinogenesis; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The early development of many mammalian tissues including the human retina is governed in part by the activities of a molecular circuit that includes members of the Six and Eya gene families. This work will yields insights into how these genes guide cells within the visual primordium to correctly adopt a retinal fate. Our studies may also provide clues to how cells react at the molecular level to the loss of the Six and Eya genes.

描述（由申请人提供）：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，该调节回路包括 Pax、Six、Eya 和 Dach 基因家族的成员。该提案特别感兴趣的是 Six 和 Eya 蛋白在视网膜中发挥的作用。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、先天性白内障以及强直性肌营养不良和鳃耳肾综合征等非视网膜缺陷。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 蛋白质则作为转录共激活剂和蛋白质酪氨酸磷酸酶。这些蛋白质家族通过形成六-Eya异二聚体进行合作，这些二聚体被认为是下游靶基因的强激活剂。这些异二聚体的活性至关重要，因为功能丧失突变可导致人类患者和小鼠模型系统的视网膜缺陷，以及果蝇（果蝇）复眼的完全消除。 Six 和 Eya 基因损伤与昆虫和哺乳动物系统中视网膜疾病的关联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所发挥的作用。果蝇正在发育的眼睛已成为研究控制组织决定的遗传和分子机制的首要模型系统。其优点包括已得到充分描述的定型发育模式、已知眼睛规格基因的大量实验数据以及大量可用的突变株和分子/细胞标记。在果蝇中，无眼是 Eya 家族的唯一成员，而 sine oculis、optix 和 DSix4 则代表 Six 基因家族。尽管人们在了解这些基因在发育中所发挥的作用方面付出了巨大努力，但仍有大量重要问题仍未得到解答。拟议工作的目标是解决这些问题并提供答案，以进一步了解 Six 和 Eya 基因在视网膜决定中所发挥的作用。在本提案中，我们将尝试确定 (1) optix 在正常眼睛发育中发挥的作用； (2) 眼正弦和缺如眼在将视网膜规格与细胞周期和组织生长联系起来方面发挥的作用； (3) 眼睛规范过程中 Sine Oculis 转录靶标的身份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、分子和生化方法以及基因组和生物信息学方法来研究这些问题。 公共健康相关性：包括人类视网膜在内的许多哺乳动物组织的早期发育部分受到包括 Six 和 Eya 基因家族成员在内的分子回路的活动的控制。这项工作将深入了解这些基因如何引导视觉原基内的细胞正确地适应视网膜命运。我们的研究还可能提供细胞如何在分子水平上对 Six 和 Eya 基因丢失做出反应的线索。