Mechanism of Action of Retinal Determination Proteins

视网膜决定蛋白的作用机制

• 批准号: 6821816
• 负责人: RASHMI S. HEGDE
• 金额: $ 33.53万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821816
• 关键词: DNA; DNA binding protein; X ray crystallography; animal tissue; binding sites; cell line; cell nucleus; chemical kinetics; cow; embryo /fetus cell /tissue; enzyme substrate; high performance liquid chromatography; intermolecular interaction; mass spectrometry; molecular assembly /self assembly; molecular shape; protein structure function; protein tyrosine phosphatase; retina; structural biology

DESCRIPTION (provided by applicant): In recent years it has become apparent that the genetic networks specifying cell-fate are conserved across species. Interestingly, these regulatory cassettes are also deployed in multiple developmental contexts, for example in the morphogenesis of different organs. An excellent example of this is the Eyeless - Eyes Absent - Sine oculis - Dachshund cascade originally described in fly eye development, and called the retinal determination pathway. An analogous pathway is involved in vertebrate eye and muscle development, and components of the network have been implicated in brain, ear, and kidney development. Mutations in these genes are associated with several human developmental diseases including bronchio-oto-renal syndrome and congenital cataracts (Eyes Absent), holoprosencephaly, bilateral anophtalmia and pituitary anomalies (mutations in the human sine oculis genes), aniridia (mutations in Pax6, the human homologoue of Eyeless), as well as postaxial polydactyly type A2, mental retardation, and a form of Bardet-Biedel syndrome (Dachshund mutations). It is our long-term goal to unravel the molecular mechanisms underlying these regulatory pathways. This proposal focuses on the two novel protein families in this network: Eyes Absent and Dachshund. We have recently obtained evidence that Eyes Absent has protein tyrosine phosphatase activity and that Dachshund contains a DNA-binding motif. These unexpected observations alter existing models for the roles of these two critical retinal determination proteins, and are the basis for the studies proposed here. We plan to use crystallography and biochemistry in an integrated effort to decipher the molecular mechanisms of Eyes Absent and Dachshund action during early embryonic development.

描述（由申请人提供）：近年来，很明显，指定细胞命运的遗传网络在物种之间是保守的。有趣的是，这些调控磁带也被部署在多种发育环境中，例如不同器官的形态发生。一个很好的例子是无眼-无眼-正弦眼-达克斯猎犬级联最初描述在苍蝇眼睛发育，并称为视网膜决定途径。在脊椎动物的眼睛和肌肉发育中也有类似的通路，而在大脑、耳朵和肾脏发育中也有类似的通路。这些基因的突变与几种人类发育疾病有关，包括细支气管-耳-肾综合征和先天性白内障（眼睛缺失）、前脑全裂、双侧眼球缺失和垂体异常（人类正眼基因突变）、无虹膜（Pax6基因突变，人类无眼基因同系物），以及轴后多指畸形A2型、智力迟钝和一种Bardet-Biedel综合征（达克斯猎犬突变）。我们的长期目标是揭示这些调控途径背后的分子机制。本研究主要关注该网络中的两个新蛋白家族：Eyes Absent和Dachshund。