Prox1 and fibroblast growth factor receptors form a novel regulatory loop controlling lens fiber differentiation and gene expression

Abstract

Lens epithelial cells differentiate into lens fibers (LF) in response to a fibroblast growth factor (FGF) gradient. 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 cell gene expression. Intriguingly, Prox1 also controlled the expression of fibroblast growth factor receptors (FGFRs) and could bind to their promoters, 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 attenuated 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.