Dominant dysplasia of the lens in transgenic mice expressing the dbl oncogene.
To study the transforming activity of the dbl oncogene and its effect on normal development in vivo, we linked dbl cDNA to promoters with different cell type specificities and used the constructs to generate transgenic mice. The promoters included the mouse alpha A-crystallin promoter, the rat insulin II promoter, and a mouse metallothionein promoter. We also generated transgenic mice carrying a recombinant cosmid clone that contains the entire dbl gene. Mice with the crystallin promoter construct developed cataracts and expressed the dbl protein in their lenses. The architecture of the lenses suggested a block to the normal pattern of differentiation and elongation of the secondary fiber cells. Mice with the insulin II promoter expressed dbl protein in the pancreas but showed no evidence of diabetes and no apparent pancreatic beta-cell defects. Similarly, mice with the metallothionein promoter expressed dbl protein in heart and testes, but showed no pathologic abnormalities in these tissues even after treatment with heavy metals. However, one family of mice carrying the metallothionein promoter construct showed cataracts and a dramatic fibroblastic dysplasia of the lens. One family with the cosmid-dbl gene showed a nearly identical lenticular dysplasia, but with a slower developmental time course. Thus, although the dbl oncogene did not induce neoplasia in any of the mice studied, it is apparently capable of interfering with the ability of the lens epithelial cells to differentiate into lens fiber cells, and of inducing metaplasia of the epithelial cells into fibroblastic cells.
Eva
A
A
Laboratory of Cellular and Molecular Biology, National Cancer Institute, Bethesda, MD 20892.
Graziani
G
G
Zannini
M
M
Merin
L M
LM
Khillan
J S
JS
Overbeek
P A
PA
D000818:Animals; D015153:Blotting, Western; D002874:Chromosome Mapping; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors; D007908:Lens, Crystalline / Q000002:abnormalities* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010375:Pedigree; D015682:Retroviridae Proteins, Oncogenic / Q000096:biosynthesis / Q000235:genetics*
D020662:Guanine Nucleotide Exchange Factors; C512843:Mcf2 protein, mouse; D015682:Retroviridae Proteins, Oncogenic