Prox1 and fibroblast growth factor receptors form a novel regulatory loop that promotes lens fiber differentiation and regulates global gene expression
Date
2015
Authors
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Publisher
University of Delaware
Abstract
Lens epithelial cells differentiate into lens fibers (LF) in response to a gradient of fibroblast growth factors (FGFs). This cell fate decision requires the transcription factor Prox1, which was hypothesized to promote cell cycle exit in differentiating lens fibers. However, conditional deletion of Prox1 from mouse lenses resulted in a failure in lens fiber differentiation despite maintenance of normal cell cycle exit. Instead, RNAseq demonstrated that Prox1 functions as a global regulator of lens fiber preferred gene expression. Intriguingly, Prox1 directly transcriptionally activate fibroblast growth factor receptors (Fgfrs), correlating with decreased downstream signaling through MAPK and AKT in Prox1 mutant lenses. Further, culturing rat lens explants in FGF increased their expression of Prox1, and this was ablated by the addition of inhibitors of MAPK. Together these results describe a novel feedback loop required for lens differentiation and morphogenesis, where Prox1 and Fgfr interact to mediate LF differentiation in response to FGF. This analysis also differentiates the role of Prox1 in controlling cell cycle exit from its requirement for lens fiber morphogenesis, which involves Prox1-mediated transcriptional upregulation of lens functional genes, and regulation of growth factor receptors. The lenses of Prox1 conditional knock-out mice (cKO) mice exhibited profound defects in lens fiber elongation, and a global transcriptomic study of differential gene expression in these lenses compared to wild types (Wts) identified numerous new cytoskeletal interacting proteins that may play a role in mediating this process. The future of this project will elucidate Prox1's requirement for the poorly understood regulation of lens fiber elongation.