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: 6669280
• 负责人: Justin P Kumar
• 金额: $ 33.03万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6669280
• 关键词: Drosophilidae; SDS polyacrylamide gel electrophoresis; arthropod genetics; biological signal transduction; developmental genetics; functional /structural genomics; gene expression; gene mutation; genetically modified animals; immunoprecipitation; molecular cloning; protein structure function; regulatory gene; retina; tissue /cell culture

DESCRIPTION (provided by applicant): One of the most exciting revelations in retinal biology is that the molecules and mechanisms that direct eye formation are conserved throughout the animal kingdom. In recent years an entire cascade of molecules and their roles in eye specification have been found to be preserved in both mammalian and invertebrate retinal systems. In addition to provoking a profound rethinking of the origins of the eye, the emerging commonality among mechanisms used in eye development allows for the use of model systems to provide insight into the development and diseases of the mammalian eye. The Sine oculis box (Six) and Eyes absent (Eya) gene families function within the signaling cascades that regulate eye and head development in both mammals and invertebrates. Bilateral anophthalmia and holoprosencephaly type 2 are caused by mutations within the human Six6 and Six3 genes, while molecular lesions within the human Eyal gene result in congenital cataracts, Branchio-Oto-Renal (BOR) and Oto-FaciaI-Cervial (OFC) syndromes. The association of Six and Eya gene lesions with eye diseases, provides us with an exciting opportunity to explore the roles played by the SIX and EYA proteins in retinogenesis. The developing eye of the fruit fly, Drosophila melanogaster, is an excellent experimental system for elucidating the genetic, molecular and biochemical mechanisms underlying the activities of the SIX and EYA proteins. In the fruit fly, the Six family is represented by the SINE OCULIS (SO) and OPTIX proteins, while the EYES ABSENT (EYA) protein is the only Eya family member. The goals of the proposed work are (1) to identify the steps in eye specification that are regulated by the Drosophila SIX and EYA family members; (2) to define the functional differences between the two fruit fly SIX proteins; (3) to understand the interactions of several signaling pathways with SO; and (4) to identify additional genes whose products participate in eye development and interact with SO. To achieve these goals, eye development will be analyzed in animals lacking both SO and EYA proteins; biochemical approaches will be used to dissect functional differences between SO and OPTIX; and the well-established techniques of Drosophila genetics will be used to define relationships between SO and other key proteins involved in eye development. Together, these approaches will provide insight into the roles of the SIX and EYA proteins in eye specification.

描述（由申请人提供）：视网膜生物学中最令人兴奋的发现之一是，指导眼睛形成的分子和机制在整个动物王国中都是保守的。近年来，在哺乳动物和无脊椎动物的视网膜系统中发现了一系列分子及其在眼睛发育中的作用。除了引发对眼睛起源的深刻反思外，在眼睛发育机制中出现的共性允许使用模型系统来深入了解哺乳动物眼睛的发育和疾病。在哺乳动物和无脊椎动物中，Sine oculis box （Six）和Eyes absent （Eya）基因家族在调节眼睛和头部发育的信号级联中起作用。双侧眼失和2型前脑全裂是由人类Six6和Six3基因的突变引起的，而人类Eyal基因的分子病变导致先天性白内障、耳-耳-肾（BOR）和耳-脸-颈（OFC）综合征。Six和Eya基因病变与眼部疾病的关联，为我们探索Six和Eya蛋白在视网膜形成中所起的作用提供了一个令人兴奋的机会。果蝇（Drosophila melanogaster）发育中的眼睛是阐明SIX和EYA蛋白活性的遗传、分子和生化机制的良好实验系统。在果蝇中，Six家族以SINE OCULIS （SO）和OPTIX蛋白为代表，而EYES ABSENT （EYA）蛋白是唯一的EYA家族成员。本研究的目标是：(1)确定由果蝇SIX和EYA家族成员调控的眼睛发育过程；(2)明确两种果蝇SIX蛋白的功能差异；(3)了解几种信号通路与SO的相互作用；(4)鉴定其产物参与眼睛发育并与SO相互作用的其他基因。为了实现这些目标，将分析缺乏SO和EYA蛋白的动物的眼睛发育；生化方法将用于解剖SO和OPTIX之间的功能差异；以及成熟的果蝇遗传学技术将用于确定SO与其他参与眼睛发育的关键蛋白质之间的关系。总之，这些方法将深入了解SIX和EYA蛋白在眼睛发育中的作用。