The growth of the mammalian lens must be regulated with precision if images are to be focused sharply on the retina. Lens growth is ultimately dependent on cell proliferation in the epithelial layer but, despite many years of study, the details of this process are poorly understood. It has proved difficult to measure cell dynamics on the spherical anterior surface of the lens. New approaches, utilizing induced expression of fluorescent proteins and in situ imaging of S-phase cells, have provided fresh insights into the kinetics of lens cell proliferation. Preliminary data suggest that most epithelial cells are located in regions of the epithelium that support cell proliferation. Long-term imaging studies have revealed that cells migrate within the epithelium and, unexpectedly, that epithelial cells undergo multiple divisions before terminally differentiating into fiber cells. As a consequence, large, cuneiform (wedge- shaped) clones of fiber cells in the adult lens are derived from individual epithelial cells. Intriguingly, cortical cataracts in humans are characterized by the presence of cuneiform opacities of unknown etiology. Epidemiological studies have identified a link between cortical cataracts and sun exposure and some investigators have suggested that UV-induced somatic mutations could contribute to cataract formation. New insights into proliferative dynamics in the lens epithelium provide an explanation for how mutations incurred in sun-exposed regions of the epithelium could manifest as cuneiform opacities in the lens fiber mass. Kinetic parameters will be collected and used to formulate a stochastic, branching process model of lens growth. A cellular model will also be developed, in which induced expression of GFP will be used as a lineage tracer to follow the fate of mutant cells. Finally, mutations in TP53, a gene commonly mutated in sun-exposed epidermis, will be used to monitor mutational load in lens epithelium and fiber cells. These experiments are expected to provide important insights into the control of lens growth and the etiology of cortical cataract in humans.

Public Health Relevance

Cortical cataract is a global health burden. This project examines the link between proliferation of cells in the lens epithelium and cataract formation. Results of this research may lead to the development of strategies to prevent or delay cataract formation.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
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Washington University
Schools of Medicine
Saint Louis
United States
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Mesa, Rosana; Tyagi, Manoj; Harocopos, George et al. (2016) Somatic Variants in the Human Lens Epithelium: A Preliminary Assessment. Invest Ophthalmol Vis Sci 57:4063-75
De Maria, Alicia; Bassnett, Steven (2015) Birc7: A Late Fiber Gene of the Crystalline Lens. Invest Ophthalmol Vis Sci 56:4823-34
Šikić, Hrvoje; Shi, Yanrong; Lubura, Snježana et al. (2015) A stochastic model of eye lens growth. J Theor Biol 376:15-31
Shi, Yanrong; De Maria, Alicia; Lubura, Snježana et al. (2015) The penny pusher: a cellular model of lens growth. Invest Ophthalmol Vis Sci 56:799-809
Mesa, Rosana; Bassnett, Steven (2013) UV-B-induced DNA damage and repair in the mouse lens. Invest Ophthalmol Vis Sci 54:6789-97
Shi, Yanrong; Tu, Yidong; Mecham, Robert P et al. (2013) Ocular phenotype of Fbn2-null mice. Invest Ophthalmol Vis Sci 54:7163-73
Shi, Yanrong; Tu, Yidong; De Maria, Alicia et al. (2013) Development, composition, and structural arrangements of the ciliary zonule of the mouse. Invest Ophthalmol Vis Sci 54:2504-15
Shi, Yanrong; De Maria, Alicia; Bennett, Thomas et al. (2012) A role for epha2 in cell migration and refractive organization of the ocular lens. Invest Ophthalmol Vis Sci 53:551-9
De Maria, Alicia; Shi, Yanrong; Luo, Xianmin et al. (2011) Cadm1 expression and function in the mouse lens. Invest Ophthalmol Vis Sci 52:2293-9
Bassnett, Steven; Shi, Yanrong (2010) A method for determining cell number in the undisturbed epithelium of the mouse lens. Mol Vis 16:2294-300

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