Retinal Cell-Fate Determination and Pattern Formation

描述(申请人提供)：果蝇的眼睛缺失(Eya)和正弦眼球(So)基因是视网膜决定(RD)网络的关键组成部分，这对果蝇和脊椎动物的正常发育都是必不可少的。EYA既是转录辅活化子，又是蛋白磷酸酶，同时编码同源结构域转录因子。这两个基因对果蝇的视网膜发育是必要的，也是充分的。此外，Eya和So蛋白在物理上相互作用，作为一种高度有效的转录复合体协同作用，调节几个器官系统的发育。脊椎动物的正常视网膜发育需要两个高度保守的SO同源物Six3和Six6。在人类中，EYA1和SIX1的突变会导致常染色体显性遗传性疾病，称为BOR(鳃-耳-肾)综合征，其特征是鳃弓异常、听力损失和肾脏缺陷。尽管它们在哺乳动物发育过程中很重要，但EYA和SO的作用机制仍不完全清楚。此外，Eya和So直接调节无意识和无感觉，这是光感受器细胞分化的第一步所必需的，在哺乳动物中高度保守。另外两个正常视网膜分化所需的保守转录调控因子，Lozenger和Groucho，似乎也受到SO的直接调控。因此，Eya和So介导了从决定到分化的转变，从而在器官发生的关键节点发挥作用。我们的建议侧重于了解这六个基因在果蝇眼这一具有良好特征的遗传系统中的作用。我们将结合遗传学、基因组学和生物化学来分析Eya和So以及ATO、SENS、Lozengg和Groucho在视网膜发育中的作用。由于遗传途径在跨越系统发育的器官形成过程中经常被保守和重复使用，研究更简单的生物体的发育可以提供对人类疾病的快速和重要的洞察。与公共健康相关：该项目的主要目标是了解眼睛缺失(Eya)和正弦眼球(So)基因在眼睛发育过程中的作用。这两个基因从果蝇到人类都高度保守，已知在包括眼睛在内的人类发育过程中发挥着重要作用。我们将利用果蝇遗传学无与伦比的力量来破译这些重要但鲜为人知的基因的功能。

DESCRIPTION (provided by applicant): The eyes absent (eya) and sine oculis (so) genes in Drosophila are key components of the retinal determination (RD) network, which is essential for normal development in both flies and vertebrates. Eya functions both as a transcriptional coactivator and a protein phosphatase while so encodes a homeodomain transcription factor. Both genes are necessary and sufficient for retinal development in Drosophila. Moreover, the Eya and So proteins physically interact and act synergistically as a highly potent transcription complex that regulates development of several organ systems. Two highly conserved homologs of so, Six3 and Six6, are required for normal retinal development in vertebrates. In humans, mutations in EYA1 and SIX1 cause the autosomal dominant disorder known as BOR (branchio-oto-renal) syndrome, characterized by branchial arch abnormalities, hearing loss, and kidney defects. Despite their importance during mammalian development, the mechanism of Eya and So action remains incompletely understood. In addition, Eya and So directly regulate atonal and senseless, which are required for the first steps in photoreceptor cell differentiation and are highly conserved in mammals. Two other conserved transcriptional regulators required for normal retinal differentiation, Lozenge and Groucho, also appear to be directly regulated by So. Thus, Eya and So mediate the transition from determination to differentiation and thereby act at a critical junction in organogenesis. Our proposal focuses on understanding the role of these six genes in a well-characterized genetic system, the Drosophila eye. We will use a combination of genetics, genomics, and biochemistry to analyze the roles of Eya and So, as well as Ato, Sens, Lozenge, and Groucho, during retinal development. Since genetic pathways are often conserved and reiteratively used during organ formation across phylogeny, studying the development of simpler organisms can provide rapid and significant insight into human disease. PUBLIC HEALTH RELEVANCE: The main goal of this project is to understand how the eyes absent (eya) and sine oculis (so) genes act during eye development. Both genes are highly conserved from fruit flies to humans and are known to play essential roles in human development, including the eye. We will use the unparalleled power of Drosophila genetics to decipher the function of these important but poorly understood genes.