Disruption of the sparc locus in mice alters the differentiation of lenticular epithelial cells and leads to cataract formation

SPARC (secreted protein acidic and rich in cysteine) is a matricellular pro tein that regulates cellular adhesion and proliferation. In this report, we show that SPARC protein is restricted to epithelial cells of the murine le ns and ends abruptly at the equatorial bow region where lens fiber differen tiation begins. SPARC protein was not detected in the lens capsule or in di fferentiated lens fibers. SPARC-null mice developed cataracts at approximat ely 3-4 months after birth, at which time posterior subcapsular opacities w ere observed by slit lamp ophthalmoscopy. Histological analyses of ocular s ections from 3-month old animals revealed several microscopic abnormalities present in the SPARC-null mice but absent from the wild-type animals. Fibe r cell elongation was incomplete posteriorly and resulted in displacement o f the lenticular nucleus to the posterior of the lens. Nuclear debris was p resent in the posterior subcapsular region of the lens, an indication of th e abnormal migration and elongation of either fetal or anterior epithelial cells, and the bow region was disrupted and vacuolated. In the anterior len s, the capsule appeared to be thickened and was lined by atypical, plump cu boidal epithelium. Moreover, anterior cortical fibers were swollen. Polyacr ylamide gel electrophoresis of the epithelial, cortical and nuclear fractio ns of wild-type and SPARC-null lenses indicated no significant differences among the alpha-, beta-, and gamma-crystallins. Expression of alpha B-cryst allin appeared similar in fiber cells of wild-type and SPARC-null lenses, a lthough the distribution of alpha B-crystallin was asymmetric in SPARC-null lenses as a result of abnormal lens fiber differentiation. No evidence of atypical extracellular matrix deposition in areas other than the capsule wa s detected in wild-type or SPARC-null lens at 3 months of age. We conclude that the disruption of the Sparc locus in mice results in the alteration of two fundamental processes of lens development: differentiation of epitheli al cells and maturation of fiber cells. (C) 1999 Academic Press.