Fibroblast growth factor receptor signaling through MEK-ERK is required for prostate bud induction

Abstract

The urogenital sinus (UGS) is specified as prostate in mice around embryonic day 15.5 as indicated by expression of the transcription factor Nkx3.1. Shortly thereafter, growth of epithelial buds into the UGS mesenchyme initiates prostatic morphogenesis. A comparison of male and female UGSs in vivo demonstrated sexually dimorphic expression of branching morphogenesis regulatory genes coincident with epithelial budding including Bmp7, Gli1, Gli2, Fgf10, Ptch1, and Shh. A comparison of UGSs grown with or without testosterone in serum-free organ cultures showed that some, but not all sexually dimorphic differences observed during prostate bud induction, were effectively modeled in vitro. Organ cultures were then used to investigate the role of fibroblast growth factor receptor (FGFR) signaling during prostatic induction. Blocking FGFR activation with PD173074 showed that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the UGS is dependent on FGFR signaling. Furthermore, inhibiting either FGFR activation with PD173074 or ERK1/2 activation with UO126 blocked all morphogenesis, proliferation, and gene expression changes induced by androgens in the UGS. These data reveal a previously unknown role for ERK1/2 during prostate bud induction. They also show that signaling by FGFRs through ERK1/2 is required for androgen-induced budding morphogenesis, proliferation, and gene expression during prostate bud induction.