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). Although a large body of evidence suggests that fibroblast growth factors (FGFs) are the signal that induces lens epithelial cells to differentiate into lens fiber cells, there is no definitive proof yet. Prior to terminal differentiation, lens epithelial cells undergo cell cycle withdrawal and remain amitotic thereafter. The central questions concerning the differentiation of lens fiber cells are as follows. 1) What is the nature of the inductive signal? 2) How is the signal transduced? What are the components of this signaling pathway? 3) How does the signal transduction pathway instruct the differentiation of lens fiber cells, manifested as cell cycle arrest, expression of lens specific genes, and dramatic morphological changes? In other words, what are the effectors of this signaling pathway? These questions remain largely unanswered due to lack of genetic approaches in mammalian systems. Through research into cell cycle regulation in mammals, we have discovered that p57KIP2, a Cdk inhibitor, is required for cell cycle arrest during the differentiation of both primary and secondary lens fiber cells. Disruption of its function leads to compromised differentiation of lens fiber cells and the formation of cataracts. This research has provided us with one critical effector of the signaling pathway. Exploration on p57's function during lens development will certainly provide some answers to the questions posted above and may shed fresh light on the cause and prevention of cataracts.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Visual Sciences A Study Section (VISA)
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Liberman, Ellen S
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Baylor College of Medicine
Schools of Medicine
United States
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Jia, Junling; Lin, Min; Zhang, Lingna et al. (2007) The Notch signaling pathway controls the size of the ocular lens by directly suppressing p57Kip2 expression. Mol Cell Biol 27:7236-47