Development of cataractous macrophthalmia in mice expressing an active MEK1 in the lens.
OBJECTIVE
To characterize the extracellular signal-regulated kinase (ERK) pathway in the lens and to try to understand how this pathway contributes to lens function and cataractogenesis.


METHODS
The members of the ERK pathway in the lens were examined by Western blotting, immunohistochemical staining, and kinase assay. A gain-of-function approach was used to perturb the ERK pathway in the lenses of transgenic mice via expression of a constitutively active mutant of the mitogen-activated protein kinase kinase 1 (MEK1(E)), the direct upstream kinase of the ERK1 and ERK2 kinases, under the alphaA-crystallin promoter.


RESULTS
The presence of an active ERK pathway was found in lens epithelial cells and in differentiating fibers. Transgenic mice that expressed MEK1(E) developed postnatal cataracts as well as macrophthalmia. Distinct morphologic alterations, such as lens enlargement, swelling fiber cells, enlarged extracellular space, and vacuole formation, were observed in the lenses of these transgenic mice. A significant increase in the glucose transporter 1 (GLUT1) level, as well as in the glucose level, was detected in the lens.


CONCLUSIONS
The MAP kinase pathway is involved in the regulation of glucose metabolism and balance in the mouse lens. Moreover, the alteration of MAP kinase activity in the lens is sufficient to cause cataract formation with enlarged extracellular space and vacuoles in the differentiating fibers. This transgenic mouse may provide a useful model for understanding the mechanism(s) for some aspects of human cataracts.
Department of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. gong@scripps.edu
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Gong
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Wang
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Han
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Niesman
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Huang
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Horwitz
D000818:Animals; D015153:Blotting, Western; D002386:Cataract / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D002454:Cell Differentiation; D003459:Crystallins / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1; D007908:Lens, Crystalline / Q000201:enzymology* / Q000473:pathology; D048369:MAP Kinase Kinase 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008850:Microphthalmos / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D015854:Up-Regulation
D003459:Crystallins; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; C495678:Slc2a1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D005947:Glucose