Characterization of the roles of STAT1 and STAT3 signaltransduction pathways in mammalian lens development

[摘要] Purpose: IGF-1 and PDGF are implicated in regulating lensproliferation and/or providing spatial cues that restrict lensproliferation to germinative and transition zones of the lens. However,very little is known about how IGF-1- or PDGF-induced signals aretransduced and coupled to gene transcription in lens cells. Therefore,we examined whether these growth factors mediate their effects in thelens through the evolutionarily conserved JAK/STAT signal transductionpathway and if STAT signaling is essential for mammalian lensdevelopment.Methods: Expression of STAT1 and STAT3 was analyzed in mouse lensand lens epithelial cells by RT-PCR and western blot analysis.Activation of the STAT signaling pathway was examined by a combinationof gel-shift, super-shift, and western blotting assays. Regulation oflens proliferation and gene transcription by STAT pathways was assessedby 3H-Thymidine incorporation or RT-PCR assays with lens explantstreated or untreated with Genistein or the JAK2 and STAT3 inhibitor,AG-490. Mice with targeted deletion of STAT3 in the lens were generatedby Cre/lox recombination and STAT1-/-, STAT3-/- deficient aswell as normal lenses were characterized by histology.Results: We show that PDGF and IGF1 induce proliferation in 1AMLE6lens cells and couple their extracellular signals to gene transcription,in part through activation of STAT3 and to a lesser extent STAT1 signaltransduction pathways. We further show that targeted deletion of STAT3in E10.5 lens does not produce overt developmental lens defects. STAT1knockout mice also exhibit a normal lens phenotype.Conclusions: Our results showing that deletion of either STAT1 orSTAT3 does not affect the normal development of the lens is surprisingin view of the fact that STAT pathways are activated in developing chickor mouse lens and inappropriate activation of STAT1 pathway in the lensby ectopic lens expression of IFNγ inhibits lens differentiationand induces cataract in transgenic mice. Our data thus suggest thatalthough STAT-signaling pathways may contribute to activation of genetranscription in the lens, it may not be essential for normal lensdevelopment or STAT proteins may be functionally redundant during lensdevelopment. However, because several growth factors and cytokinespresent in the lens activate STATs in mouse lens explants and 1AMLE6lens epithelial cells, it may well be that this evolutionarily conservedsignaling pathway is under stringent control in the mammalian lens.Whereas deficiency in any particular STAT pathway can be compensated forby any of the functionally redundant STAT proteins induced by a widearray of growth factors in the lens, chronic or prolonged activation ofa particular STAT protein may perturb homeostatic balance inSTAT-dependent growth factor signaling, culminating in pathologic lenschanges.

[学科分类] 生物化学/生物物理