Loss of AND-34/BCAR3 expression in mice results in rupture of the adult lens.
OBJECTIVE
AND-34/BCAR3 (Breast Cancer Anti-Estrogen Resistance 3) associates with the focal adhesion adaptor protein, p130CAS/BCAR1. Expression of AND-34 regulates epithelial cell growth pattern, motility, and growth factor dependence. We sought to establish the effects of the loss of AND-34 expression in a mammalian organism.


METHODS
AND-34(-/-) mice were generated by homologous recombination. Histopathology, in situ hybridization, and western blotting were performed on murine tissues.


RESULTS
Western analyses confirmed total loss of expression in AND-34(-/-) splenic lymphocytes. Mice lacking AND-34 are fertile and have normal longevity. While AND-34 is widely expressed in wild type mice, histologic analysis of multiple organs in AND-34(-/-) mice is unremarkable and analyses of lymphocyte development show no overt changes. A small percentage of AND-34(-/-) mice show distinctive small white eye lesions resulting from the migration of ruptured cortical lens tissue into the anterior chamber. Following initial vacuolization and liquefaction of the lens cortex first observed at postnatal day three, posterior lens rupture occurs in all AND-34(-/-) mice, beginning as early as three weeks and seen in all mice at three months. Western blot analysis and in situ hybridization confirmed the presence of AND-34 RNA and protein in lens epithelial cells, particularly at the lens equator. Prior data link AND-34 expression to the activation of Akt signaling. While Akt Ser 473 phosphorylation was readily detectable in AND-34(+/+) lens epithelial cells, it was markedly reduced in the AND-34(-/-) lens epithelium. Basal levels of p130Cas phosphorylation were higher in AND-34(+/+) than in AND-34(-/-) lens epithelium.


CONCLUSIONS
These results demonstrate the loss of AND-34 dysregulates focal adhesion complex signaling in lens epithelial cells and suggest that AND-34-mediated signaling is required for maintenance of the structural integrity of the adult ocular lens.
Department of Medicine, Boston Medical Center, Boston, MA 2118, USA.
Richard I
RI
Near
Richard S
RS
Smith
Paul A
PA
Toselli
Thomas F
TF
Freddo
Alexander B
AB
Bloom
Pierre
P
Vanden Borre
David C
DC
Seldin
Adam
A
Lerner
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000831:Animals, Newborn; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D007908:Lens, Crystalline / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009928:Organ Specificity; D016612:Paraffin Embedding; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012422:Rupture, Spontaneous / Q000473:pathology; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C120867:Bcar3 protein, mouse; D050719:Crk-Associated Substrate Protein; D020662:Guanine Nucleotide Exchange Factors; D012333:RNA, Messenger; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt