Activation of the Jak-STAT-signaling pathway in embryonic lens cells

Previous studies showed that lens epithelial cells proliferate rapidly in t he embryo and that a lens mitogen, most likely derived from the blood, is p resent in the anterior chamber of the embryonic eye (Hyatt, G. A., and Beeb e, D. C., Development 117, 701-709, 1993). Messenger RNAs for several growt h factor receptors have been identified in embryonic lens epithelial cells. We tested several growth factors that are ligands for these receptors for their ability to maintain lens cell proliferation. Embryo serum, PDGF, GM-C SF, and G-CSE maintained lens cell proliferation, but NGF, VEGF, and HGF di d not. This and a previous study (Potts, J. D., Harocopos, G. J., and Beebe , D. C., Curr. Eye Res. 12, 759-763, 1993) detected members of the Janus ki nase family (Jaks) in the developing lens. Because Jaks are central players in the Tak-STAT-signaling pathway, we identified STAT proteins in the lens and tested whether they were phosphorylated in response to mitogens. STAT1 and STAT3, but not STAT5 were detected in chicken embryo lens epithelial c ells. Only STAT3 was found in terminally differentiated lens fiber cells. S TAT1 and STAT3 were phosphorylated in lens cells analyzed immediately after removal from the embryo and when lens epithelial explants were treated wit h embryo serum, PDGF, or GM-CSF, but not with NGF. Chicken embryo vitreous humor or IGF-1, factors that stimulate lens cell differentiation, but not p roliferation, did not cause STAT phosphorylation. When lens epithelial cell s were cultured for 4 h in unsupplemented medium, STAT1 and STAT3 declined to nearly undetectable levels. Treatment with PDGF or embryo serum for an a dditional 15 min restored STAT1 and -3 levels. This recovery was blocked by cycloheximide, but not actinomycin D, suggesting that STAT levels are regu lated at the level of translation. STAT levels were maintained in epithelia l explants by lens mitogens, but not by factors that stimulated lens fiber differentiation. Both factors that stimulated lens cell proliferation and t hose that caused fiber differentiation protected cultured lens epithelial c ells from apoptosis. These data suggest that the factor(s) responsible for lens cell proliferation in vivo activates the Jak-STAT-signaling pathway. T hey also indicate that growth factors maintain STAT protein levels in lens epithelial cells by promoting the translation of STAT mRNA, an aspect of ST AT regulation that has not been described previously. Signaling by most of the growth factors and cytokines known to activate the Jak-STAT pathway has been disrupted in mice by mutation or targeted deletion. Consideration of the phenotypes of these mice suggests that the factor responsible for lens cell proliferation in vivo may be a growth factor or cytokine that has not yet been described. (C) 1998 Academic Press.