Regulation Of Cytokine Signaling Pathways In The Eye

Egwuagu, Charles

Abstract

Factors responsible for lens proliferation activate the JAK/STAT signaling pathway in embryonic chicken lens. STAT3 is expressed in chicken lens epithelia and fibers. Cultured chicken lens epithelia responds to PDGF stimulation by activation (tyrosine phoshorylation) of STAT3, suggesting a possible role of STAT3 in lens development. The goal of our study is to investigate whether mammalian lens cells also respond to growth factors implicated in lens growth and differentiation by activating STAT3 and whether STAT3 is essential for lens development. Three well characterized lens cell lines (CRLE2, 1AMLE6, and NKR-11) were treated with PDGF or IGF1 for 2 hrs. Extracts from the lens cells were analyzed for STAT3 activation by Western blotting and gel-shift assays. Mice with targeted deletion of STAT3 in the lens were generated by Cre/lox recombination and the phenotypes of the lenses characterized by RT-PCR, Western blotting and histology. STAT3 expression was detected in all lens cell lines examined. We found activation of STAT3 in response to factors that stimulate proliferation as well as those that induce differentiation (IGF1). This is in contrast to chicken lens cells in which activation of STAT3 was only by PDGF and not IGF1. Surprisingly, mice with lens specific deletion of STAT3 have a normal lens phenotype. reveal that IGF1 and PDGF signaling in the mammalian lens are mediated by STAT3. However, targeted deletion of STAT3 in the lens during embryonic development does not cause abnormal lens phenotype, suggesting that STAT3 signaling is not essential, at least for mammalian lens development. As PDGF and IGF1 mediate their effects primarily through STAT3, our data further suggest that IGF1 and PDGF are either not essential for lens growth and differentiation or that their contributions to these processes are redundant.