Activated Ras induces lens epithelial cell hyperplasia but not premature differentiation.
Growth factor signaling is implicated in the regulation of lens cell proliferation and differentiation during development. Activation of growth factor receptor tyrosine kinases is known to activate Ras proteins, small GTP-binding proteins that function as part of the signal transduction machinery. In the present study, we examined which classical Ras genes are expressed in lens cells during normal development and whether expression of an activated version of Ras is sufficient to induce either lens cell proliferation or fiber cell differentiation in transgenic mice. In situ hybridization showed H-Ras, K-Ras and N-Ras are ubiquitously expressed in all cells of the embryonic (E13.5) eye, with N-Ras showing the highest level of expression. The expression level of N-Ras decreases during later stages of embryonic development, and is nearly undetected in postnatal day 21 lenses. To generate transgenic mice, a constitutively active H-Ras mutant was linked to a chimeric regulatory element containing the mouse alphaA-crystallin promoter fused to the chick delta1-crystallin lens enhancer element. In the lenses of the transgenic mice, the transgene was expressed in both lens epithelial and fiber cells. Expression of activated Ras was sufficient to stimulate lens cell proliferation but not differentiation, implying that alternative or additional signal transduction pathways are required to induce fiber cell differentiation.
Reneker
Lixing W
LW
Department of Ophthalmology, School of Medicine, University of Missouri, Columbia, Missouri, USA. renekerl@health.missouri.edu
Xie
Leike
L
Xu
Li
L
Govindarajan
Venkatesh
V
Overbeek
Paul A
PA
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D049109:Cell Proliferation; D004396:Coloring Agents / Q000494:pharmacology; D004742:Enhancer Elements, Genetic; D004847:Epithelial Cells / Q000473:pathology*; D005136:Eye Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006965:Hyperplasia; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013997:Time Factors; D019076:Transgenes; D038207:delta-Crystallins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D000963:Antimetabolites; D004396:Coloring Agents; D005136:Eye Proteins; D007381:Intermediate Filament Proteins; D018809:Proliferating Cell Nuclear Antigen; D038207:delta-Crystallins; C079098:filensin; D019204:GTP-Binding Proteins; D018631:ras Proteins; D001973:Bromodeoxyuridine