Lens-specific expression of transforming growth factor beta1 in transgenic mice causes anterior subcapsular cataracts.

Abstract

Transgenic mice were generated by microinjection of a construct containing a self-activating human TGF-beta1 cDNA driven by the lens-specific alphaA-crystallin promoter. Seven transgenic founder mice were generated, and four transgenic lines expressing TGF-beta1 were characterized. By postnatal day 21, mice from the four families exhibited anterior subcapsular cataracts. The lenses in these mice developed focal plaques of spindle-shaped cells that expressed alpha-smooth muscle actin, and that resembled the plaques seen in human anterior subcapsular cataracts. Transgenic mice showed additional ocular defects, including corneal opacification and structural changes in the iris and ciliary body. The corneal opacities were associated with increased exfoliation of the squamous layer of the corneal epithelium and increased DNA replication in the basal epithelium.

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

“…Elevated levels of this protein were observed in Prdx6 À/À cells ( Figure 2B, d, lane 2), suggesting a TGFb-mediated effect. In view of our previous report 29 and data from other laboratories, [44][45][46] we hypothesize that phenotypic changes and expression of a-sm actin in PRDX6-depleted LECs are associated with TGFb. Initially, we verified the presence of TGFb RI 29 and RII 47 receptors in Prdx6 À/À LECs by Western analysis (data not shown).…”

“…Moreover, lens-specific expression of TGFb1 in transgenic mice induces anterior subcapsular cataracts. 46 These include phenotypic changes, apoptosis, and expression of a-SM actin, similar to those observed in human cataract. Interestingly, if TGFb is injected into the vitreous or aqueous chamber of rat eye in vivo, the most pronounced changes occur at the bow region of the lens, initiating more typical cortical cataract.…”

α-Smooth muscle actin is constitutively expressed in the lens epithelial cells of several species

“…The α-SMA antibody used in our studies is a mouse monoclonal antibody, clone 1A4, which is widely used as a marker to study smooth muscle differentiation and myofibroblast formation (Skalli et al, 1986). This antibody is commonly used to identify myofibroblast formation in the lens (Lovicu et al, 2002;Nagamoto et al, 2000;Srinivasan et al, 1998). Culturing epithelial explants in defined medium, a treatment that leads to myofibroblast formation, caused a large increase in α-SMA accumulation.…”

Matrix metalloproteinases as mediators of primary and secondary cataracts

“…Biologically active TGF-β has been detected in the ocular media from patients suffering with cataracts and is considered to be the likely trigger in human ASC formation [38,39]. Multiple in vitro and in vivo models of TGF-β-induced ASC have also been developed, including a transgenic mouse model in which active TGF-β is ectopically expressed in lens fiber cells, under the control of the α-A crystallin promoter [40]. In these mice, the ASCs formed closely resemble those observed in humans.…”