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: 8694777
• 负责人: Justin P Kumar
• 金额: $ 39万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694777
• 关键词: Adopted; Adult; Affect; Anophthalmos; Bilateral; Binding; Biological Models; Brain; Branchio-Oto-Renal Syndrome; C-terminal binding protein; Cells; Complex; Data; Defect; Development; Disease; Drosophila eye; Drosophila genus; Drosophila melanogaster; Enhancers; Erinaceidae; Event; Eye; Eye Development; Family; Gene Expression; Gene Family; Gene Targeting; Genes; Genetic Enhancer Element; Genetic Processes; Genetic Transcription; Goals; Gonadal structure; Head; Health; Holoprosencephaly; Homeodomain Proteins; Homologous Gene; Human; Insecta; Instruction; Lead; Lesion; Malignant Neoplasms; Mesoderm; Molecular; Molecular Genetics; Mutation; Myotonic Dystrophy; Organ; Pathway interactions; Patients; Pattern; Pattern Formation; Phenotype; Play; Primordium; Protein Tyrosine Phosphatase; Proteins; Reporting; Research; Retina; Retinal; Retinal Diseases; Role; Signal Pathway; Signal Transduction; System; Tissues; Transcription Coactivator; Twin Multiple Birth; Vertebrates; Visual; Work; compound eye; congenital cataract; eye formation; eye primordia; insight; interest; lens; member; mouse model; mutant; novel; public health relevance; retinal progenitor cell; tool; transcription factor; tumorigenesis

Project Summary The early development of a number of insect and mammalian tissues including the eye requires 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 early formation and initial patterning of the retina. The function of these two gene families are highly significant to human health as mutations can lead to holoprosencephaly with associated cyclopia, bilateral anophthalmia and 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 are homeobox containing transcription factors whereas EYA proteins have transcriptional co-activator and protein tyrosine phosphatase activities. These proteins regulate the transcription of target genes as SIX-EYA heterodimers. Disruption of these complexes, in addition to causing retinal disorders in both mouse models and human patients, leads to a complete block in retinal development in Drosophila melanogaster. The fruit fly eye has become a premier model system for studying the genetic and molecular mechanisms that govern tissue determination. We will take advantage of the no-eye phenotypes caused by mutations in the sine oculis (so) and eyes absent (eya) genes (the founding members of the SIX and Eya gene families) to investigate novel activities of the So-Eya complex. The ability of this complex to also coax non-ocular tissue into adopting an eye fate (ectopic eyes) is another tool that can be utilized to dissect the roles that these proteins play in early retinal determination and patterning. In this application I propose to (1) study a novel mechanism by which the So-Eya complex represses transcription of non-ocular selector genes during early eye formation; (2) identify transcription factors that bind to and activate recently identified novel enhancers of the eya gene; and (3) determine the molecular and functional relationships between the So-Eya complex and the Decapentaplegic (Dpp) signaling pathway. The association of SIX and EYA gene lesions with retinal disorders in both insect and mammalian systems provides us with an exciting opportunity for studies in the Drosophila eye to advance our understanding of mammalian eye formation and human retinal disorders.

项目摘要 包括眼睛在内的许多昆虫和哺乳动物组织的早期发育需要 包括PAX、SIX、EYA成员的进化上保守的调节回路的活性 DACH基因家族该提议特别感兴趣的是SIX和EYA蛋白的作用， 在视网膜的早期形成和初始图案中起作用。这两个基因家族的功能 对人类健康非常重要，因为突变可导致前脑无裂畸形， 独眼畸形、双眼无眼症和先天性白内障以及非视网膜缺陷， 强直性肌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。SIX蛋白是含有转录因子的同源框 而EYA蛋白具有转录共激活因子和蛋白酪氨酸磷酸酶活性。 这些蛋白质作为SIX-EYA异二聚体调节靶基因的转录。破坏这些 复合物，除了在小鼠模型和人类患者中引起视网膜疾病外，还导致 黑腹果蝇视网膜发育的一种完全阻断。果蝇的眼睛已经变成了 用于研究控制组织的遗传和分子机制的首要模型系统 保持战略定力我们将利用无眼表型所造成的突变，在正弦眼 (so)和眼睛缺失（Eya）基因（SIX和Eya基因家族的创始成员）， 研究So-Eya复合物的新活性。这种复合物也能诱导非视觉 另一个可以用来分析眼睛的角色的工具是将一个组织移植到一个眼睛的命运中（异位眼）。 这些蛋白质在早期视网膜决定和模式中发挥作用。在本申请中，我建议（1） 研究So-Eya复合物抑制非眼选择因子转录的新机制 在早期眼睛形成过程中的基因;（2）识别最近结合并激活的转录因子 鉴定Eya基因的新增强子;和（3）确定Eya基因的分子和功能增强子。 So-Eya复合物和十肢麻痹（Dpp）信号通路之间的关系。的 昆虫和哺乳动物系统中SIX和EYA基因损伤与视网膜疾病的关系 为我们研究果蝇眼睛提供了一个令人兴奋的机会， 哺乳动物眼睛的形成和人类视网膜疾病。