Role of the Lens1/Foxe3 Gene Family in Lens Formation

描述（由申请人提供）：晶状体的形成需要几个信号分子和转录调节因子的相互作用。其中之一是小鼠叉头蛋白Foxe3及其爪蟾功能同源物Xlens1。我们之前已经证明Foxe3在晶状体形成的早期阶段表达，Foxe3的突变是小鼠晶状体发育不良（dyl）表型的原因。人类FOXE3基因突变可导致前段发育不良和白内障。Xlens1过表达干扰晶状体纤维细胞的正常分化，导致晶状体前上皮细胞过度增殖。本研究的目的是确定Foxe3/Lens1基因家族的功能和调控元件。我们提出以下与晶状体形成有关的具体目标。

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.