Role of the Lens1/Foxe3 Gene Family in Lens Formation

Lens1/Foxe3 基因家族在晶状体形成中的作用

• 批准号: 6896171
• 负责人: MILAN Alexander JAMRICH
• 金额: $ 33.86万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6896171
• 关键词: Xenopus oocyte; anterior chamber; clinical research; developmental genetics; eye disorder; gene mutation; genetically modified animals; histogenesis; human subject; in situ hybridization; laboratory mouse; lens; vertebrate embryology

DESCRIPTION (provided by applicant): Lens formation requires the interaction of several signaling molecules and transcriptional regulators. One of them is the murine forkhead protein Foxe3 and its Xenopus functional homologue Xlens1. We have shown previously that Foxe3 is expressed during the earliest stages of lens formation, and mutations in Foxe3 are the cause of the dysgenetic lens (dyl) phenotype in mouse. Mutations in human FOXE3 can cause anterior segment dysgenesis and cataracts. Overexpression of Xlens1 interferes with normal differentiation of lens fiber cells and results in overproliferation of cell in the anterior lens epithelium. The goal of this research is to identify the function and regulatory elements of Foxe3/Lens1 gene family. We propose the following specific aims related to lens formation. Specific Aim 1: Characterization of proteins that are involved in regulation of Foxe3 transcription. The goal of this specific aim is to isolate proteins that bind to the Foxe3 regulatory region and therefore are likely to be direct regulators of Foxe3 transcription. Specific Aim 2. Analysis of lens development in the absence of Foxe3/Xlens 1 function. The effects of elimination of Foxe3 function on development of the lens and on lens specific gene expression will be monitored in Foxe3 "knockout" mice. Elimination of Xlens1 function will be achieved by injection of Xenopus embryos with morpholinos directed against the translation initiation region of Xlens1. These experiments will determine the consequences of elimination of Xlens1 activity on development of structures derived from the anterior placodal region. Specific Aim 3. Correction of molecular and phenotypic defects in dysgenetic lens mutant mice by intrauterine gene transfer. In order to achieve this goal, we will introduce the wild type Foxe3 gene into dysgenetic lens embryos using viral vectors. These vectors will carry the wild type Foxe3 regulatory and coding sequences and will be delivered to the mutant embryos via intrauterine gene transfer.

描述（由申请人提供）：透镜的形成需要几种信号分子和转录调节因子的相互作用。其中之一是鼠叉头蛋白Foxe 3及其爪蟾功能同源物Xlens 1。我们先前已经表明Foxe 3在透镜形成的最早阶段表达，Foxe 3的突变是小鼠遗传不良透镜（dyl）表型的原因。人类FOXE 3突变可导致眼前节发育不全和白内障。Xlens 1的过表达干扰了透镜纤维细胞的正常分化，并导致前透镜上皮细胞过度增殖。本研究的目的是鉴定Foxe 3/Lens 1基因家族的功能和调控元件。我们提出以下与透镜形成相关的具体目标。 具体目标1：参与Foxe 3转录调控的蛋白质的表征。该特定目标的目的是分离与Foxe 3调节区结合的蛋白质，因此可能是Foxe 3转录的直接调节因子。 具体目标2。Foxe 3/X透镜1功能缺失时透镜发育的分析。将在Foxe 3“敲除”小鼠中监测Foxe 3功能消除对透镜发育和对透镜特异性基因表达的影响。Xlens 1功能的消除将通过向非洲爪蟾胚胎注射针对Xlens 1翻译起始区的吗啉代来实现。这些实验将确定消除Xlens 1活性对来自前基板区域的结构发育的影响。 具体目标3。宫内基因转移对遗传缺陷透镜突变小鼠分子和表型缺陷的矫正。为了实现这一目标，我们将使用病毒载体将野生型Foxe 3基因导入发育不良的透镜胚胎中。这些载体将携带野生型Foxe 3调控和编码序列，并将通过子宫内基因转移递送到突变胚胎中。