Loss of AND-34/BCAR3 expression in mice results in rupture of the adult lens

[摘要] Purpose: AND-34/BCAR3 (Breast CancerAnti-Estrogen Resistance 3) associates with the focal adhesion adaptorprotein, p130CAS/BCAR1. Expression of AND-34 regulates epithelial cellgrowth pattern, motility, and growth factor dependence. We sought toestablish the effects of the loss of AND-34 expression in a mammalianorganism. Methods: AND-34−/−mice were generated by homologous recombination. Histopathology, insitu hybridization, and western blotting were performed on murinetissues. Results: Western analyses confirmedtotal loss of expression in AND-34−/− spleniclymphocytes. Mice lacking AND-34 are fertile and have normal longevity.While AND-34 is widely expressed in wild type mice, histologic analysisof multiple organs in AND-34−/− mice is unremarkableand analyses of lymphocyte development show no overt changes. A smallpercentage of AND-34−/− mice show distinctive smallwhite eye lesions resulting from the migration of ruptured corticallens tissue into the anterior chamber. Following initial vacuolizationand liquefaction of the lens cortex first observed at postnatal daythree, posterior lens rupture occurs in all AND-34−/−mice, beginning as early as three weeks and seen in all mice at threemonths. Western blot analysis and in situ hybridization confirmed thepresence of AND-34 RNA and protein in lens epithelial cells,particularly at the lens equator. Prior data link AND-34 expression tothe activation of Akt signaling. While Akt Ser 473 phosphorylation wasreadily detectable in AND-34+/+ lens epithelial cells, itwas markedly reduced in the AND-34−/− lensepithelium. Basal levels of p130Cas phosphorylation were higher inAND-34+/+ than in AND-34−/− lensepithelium. Conclusions: These results demonstratethe loss of AND-34 dysregulates focal adhesion complex signaling inlens epithelial cells and suggest that AND-34-mediated signaling isrequired for maintenance of the structural integrity of the adultocular lens.

[学科分类] 生物化学/生物物理