Mechanism of Action of Retinal Determination Proteins

视网膜决定蛋白的作用机制

• 批准号: 7123809
• 负责人: RASHMI S. HEGDE
• 金额: $ 32.74万
• 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/7123809
• 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间是保守的。有趣的是，这些调控盒也被部署在多种发育环境中，例如在不同器官的形态发生中。这方面的一个很好的例子是无眼-无眼- Sine oculis - Dachshund级联反应，最初在蝇眼发育中描述，并称为视网膜决定途径。一个类似的途径涉及脊椎动物的眼睛和肌肉发育，该网络的组成部分涉及大脑，耳朵和肾脏的发育。这些基因的突变与几种人类发育疾病有关，包括支气管-耳-肾综合征和先天性白内障（眼睛缺失）、前脑无裂畸形、双侧无眼症和垂体异常（人类sine oculis基因突变），无虹膜（Pax 6突变，无眼的人类同源物），以及轴后多指（趾）畸形A2型，精神发育迟滞，和一种Bardet-Biedel综合征（腊肠突变）。我们的长期目标是解开这些调控途径的分子机制。该提案重点关注该网络中的两个新蛋白质家族：Eyes Absent和Dachshund。 我们最近获得的证据表明，眼睛缺席有蛋白酪氨酸磷酸酶活性，腊肠犬含有DNA结合基序。这些意想不到的观察改变了现有的模型，这两个关键的视网膜决定蛋白的作用，是这里提出的研究的基础。我们计划使用晶体学和生物化学在一个综合的努力，以破译眼睛缺席和腊肠犬行动在早期胚胎发育的分子机制。