Function of the Six and Eya Genes in Retinal Development

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 进化上保守的调节回路的活动，包括PAX，Six，EYA成员 和DACH基因家族。对这项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最初的图案形成过程中发挥作用。这两个基因家族的功能 对人类健康具有非常重要的意义，因为突变可导致全前脑畸形与相关的 屈光不正、双眼无眼、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，这些基因还与 肿瘤发生和众多癌症。六种蛋白质是含有转录因子的同源盒 而EYA蛋白具有转录共激活因子和蛋白酪氨酸磷酸酶活性。 这些蛋白质以6-EYA异源二聚体的形式调节靶基因的转录。对这些的破坏 复合体除了在小鼠模型和人类患者中引起视网膜疾病外，还导致 果蝇视网膜发育完全受阻。果蝇眼已经变成了 用于研究支配组织的遗传和分子机制的主要模型系统 决心。我们将利用正弦眼球突变引起的无眼表型 (So)和眼睛缺失(Eya)基因(六和eya基因家族的创始成员)到 调查苏雅情结的新奇活动。这种复合体还具有诱骗非眼球的能力 组织通过眼睛的命运(异位眼睛)是另一个可以用来剖析角色的工具 这些蛋白质在视网膜早期的决定和构图中起作用。在本申请中，我建议(1) So-Eya复合体抑制非眼选择素转录的新机制研究 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 确定了eya基因的新增强子；以及(3)确定了分子和功能 So-Eya复合体与十足瘫痪(DPP)信号通路的关系这个 昆虫和哺乳动物系统中Six和EYA基因突变与视网膜疾病的关系 为我们提供了一个研究果蝇眼睛的令人兴奋的机会，以增进我们对 哺乳动物的眼睛结构和人类的视网膜疾病。

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.