Role of the Lens1/Foxe3 Gene Family in Lens Formation

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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 Xlensl. 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 Xlensl 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/Lensl 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 Xlensl function will be achieved by injection of Xenopus embryos with morpholinos directed against the translation initiation region of Xlensl. These experiments will determine the consequences of elimination of Xlensl 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.