Mesenchymal WNT signaling coordinates epithelial and mesenchymal differentiation in the developing murine ureter

The coordinated development of the mesenchymal and epithelial primordia of the murine ureter requires intense tissue communication. Previous studies have revealed the crucial role of the FGFR2-SHH-FOXF1-BMP4 signaling axis in the proliferation and differentiation programs of both the epithelium and the mesenchyme. Canonical (β-Catenin/CTNNB1-dependent) WNT signaling in the mesenchymal primordium has been reported to influence mesenchymal development by enhancing proliferation and favoring the smooth muscle cell fate over adventitial fibrocytes.

To investigate the role of mesenchymal WNT signaling in early ureter development further, we analyzed the ureters of Ctnnb1-deficient mouse mutants for cellular and molecular changes during embryogenesis. Using pharmacological inhibition and activation approaches in explant cultures of embryonic ureters, we assessed the contribution of altered signaling activities to differentiation changes in Ctnnb1-deficient ureters. Transcriptional profiling of embryonic ureters with short-term WNT signaling inhibition allowed us to identify the primary targets of this signaling pathway in the ureteric mesenchyme.

We demonstrate that both mesenchymal and epithelial differentiation are impaired in ureters lacking mesenchymal Ctnnb1. This defect is linked to an inability to activate pro-differentiation transcription factors in either tissue primordia. Epithelial changes can be attributed, at least in part, to the loss of BMP4 signaling and the gain of canonical WNT signaling in the epithelial primordium. Mesenchymal WNT signaling directly activates transcription of multiple components of the SHH-FOXF1-BMP4 signaling axis, thereby enhancing this module in the inner region of the ureteric mesenchyme.

Our work improves the understanding of the signaling network that coordinates cytodifferentiation in the early ureter. Mesenchymal WNT signaling plays a central role in mesenchymal fate decisions but also in promoting epithelial differentiation through enhancement of the SHH-FOXF1-BMP4 axis and inhibition of epithelial WNT-signaling.