Retinal Cell-Fate Determination and Pattern Formation

点击翻译按钮获取中文摘要

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.