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保守的调控回路的活动，该回路包括Pax、Six、Eya和Dach基因家族的成员。这个提议特别感兴趣的是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，因为某些基因的突变可导致前脑畸形、双侧无眼症、先天性白内障以及非视网膜缺陷，如肌强直性营养不良和支耳肾综合征。此外，这些基因也与肿瘤发生和许多癌症有关。6种蛋白作为含有转录因子的同源盒，而Eya蛋白作为转录辅激活因子和蛋白酪氨酸磷酸酶。这些蛋白家族合作形成6 - eya异源二聚体，被认为是下游靶基因的强激活剂。这些异源二聚体的活性是至关重要的，因为功能丧失突变可以导致人类患者和小鼠模型系统的视网膜缺陷，以及果蝇（Drosophila melanogaster）复眼的完全消除。在昆虫和哺乳动物系统中，Six和Eya基因病变与视网膜疾病的关联为我们进一步探索这些因素在视网膜发生中的作用提供了一个令人兴奋的机会。果蝇发育中的眼睛已经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。其优势包括：已被很好地描述的刻板的发育模式，已知眼睛特征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，eyes absent是Eya家族的唯一成员，而sine oculis、optix和DSix4则代表Six基因家族。尽管在理解这些基因在发育中所起的作用方面已经做出了巨大的努力，但仍有大量重要的问题尚未得到解答。这项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的作用。在本提案中，我们将试图确定(1)optix在正常眼睛发育中所起的作用；(2)正眼和缺眼在连接视网膜规格与细胞周期和组织生长方面所起的作用；(3) Sine Oculis在眼部发育过程中转录靶点的身份及其对其调控的影响。为了解决这些问题，我们将使用遗传、分子和生化方法的创造性混合以及基因组和生物信息学方法来研究这些问题。