The mammalian lens is a relatively simple organ composed of terminally differentiated and amitotic lens fiber cells capped on the anterior surface by a layer of immature, mitotic epithelial cells. Development of the lens can be divided into two stages. The first stage results in the formation of the lens vesicle and the second stage involves growth and differentiation of the lens vesicle. The lens vesicle is derived from the head ectoderm in a region called lens placode. Under the induction of optic vesicle (the future retina), the lens placode invaginates and eventually pinches off the head ectoderm to form a single cell layered sphere, the lens vesicle. Cells in the posterior portion (those facing optic vesicle or retina) of the lens vesicle differentiate into primary lens fiber cells. The anterior portion of the lens vesicle remains as an undifferentiated epithelium. At the second stage of lens development, the epithelial cells continue to proliferate in a region slightly anterior to the lens equator and the progeny of these proliferative epithelial cells differentiate into lens fiber cells (secondary lens fiber cells) at the equator (bow region). Formation of lens fiber cells from lens epithelial cells involves dramatic changes in cell size and shape. These changes are brought about by transcriptional reprogramming of the lens epithelial cells. NEI has funded us to identify, in a large scale, genes that are reprogrammed during the differentiation of lens fiber cells. This proposal seeks funding for developing an alternative technology to generate mice deficient in specific gene functions. This technology should produce mutant mice at a fraction of the cost and time associated with conventional knockout. With this technology, we would be able to study the function of genes identified in our large scale screening in a high throughput manner, leading to a better understanding of the lens development and the disease mechanisms of the lens. Furthermore, the technology will benefit the vision research community as a whole.
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