Canonical Wnt signaling regulates smooth muscle precursor development in the mouse ureter

Abstract

SUMMARYSmooth muscle cells (SMCs) are a key component of many visceral organs, including the ureter, yet the molecular pathways that regulate their development from mesenchymal precursors are insufficiently understood. Here, we identified epithelial Wnt7b and Wnt9b as possible ligands of Fzd1-mediated -catenin (Ctnnb1)-dependent (canonical) Wnt signaling in the adjacent undifferentiated ureteric mesenchyme. Mice with a conditional deletion of Ctnnb1 in the ureteric mesenchyme exhibited hydroureter and hydronephrosis at newborn stages due to functional obstruction of the ureter. Histological analysis revealed that the layer of undifferentiated mesenchymal cells directly adjacent to the ureteric epithelium did not undergo characteristic cell shape changes, exhibited reduced proliferation and failed to differentiate into SMCs. Molecular markers for prospective SMCs were lost, whereas markers of the outer layer of the ureteric mesenchyme fated to become adventitial fibroblasts were expanded to the inner layer. Conditional misexpression of a stabilized form of Ctnnb1 in the prospective ureteric mesenchyme resulted in the formation of a large domain of cells that exhibited histological and molecular features of prospective SMCs and differentiated along this lineage. Our analysis suggests that Wnt signals from the ureteric epithelium pattern the ureteric mesenchyme in a radial fashion by suppressing adventitial fibroblast differentiation and initiating smooth muscle precursor development in the innermost layer of mesenchymal cells.

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

“…Another important observation from these studies is that conditional genetic depletion of BMPR2, stabilization of β-catenin in ABCG2 + MPCs, as well as bleomycin injury in vivo resulted in expansion of the progenitor pool, while terminal contractile function was not achieved. Previous studies have also reported the expansion of undifferentiated progenitor pools in other systems as a result of genetic depletion of BMPR, a decrease of BMP signaling, or an increase of β-catenin activation (80)(81)(82)(83)(84)(85)(86)(87)(88). Conditionally decreased BMPR signaling in adult mice drove the expansion of progenitor pools in which terminal differentiation in multiple cell types was inhibited via the activation of β-catenin signaling (80)(81)(82).…”

“…In contrast, increased noncanonical Wnt signaling in endothelial cells increases their survival and decreases vascular pruning in vivo and in vitro (94). Canonical Wnt/β-catenin signaling is required for SMC development and terminal differentiation, while in the absence of SMC differentiation, adventitial precursors may proliferate (85). These studies illustrated that a differentiation defect in perivascular cells influences the surrounding mesenchyme as well as fibroblast specification, further illustrating the cell-specific and complex nature of Wnt signaling during vascular homeostasis.…”

“…Conditionally decreased BMPR signaling in adult mice drove the expansion of progenitor pools in which terminal differentiation in multiple cell types was inhibited via the activation of β-catenin signaling (80)(81)(82). β-Catenin signaling has also been identified as an essential component of stem cell, mesenchymal cell, and SMC proliferation and differentiation in multiple models of development (83)(84)(85)(86)(87)(88). Therefore, the effects of Wnt/β-catenin activation are specific to the cell type, stage of differentiation, and the factors present in the microenvironment.…”

Smad4 Regulates Ureteral Smooth Muscle Cell Differentiation during Mouse Embryogenesis

“…Myocd , a critical transcription factor required for expression of SMC contractile proteins (αSMA, SM22α and SM-MHC) [37], is dramatically down-regulated in the mutant ureters. Ureter SMC developmental defects are highly associated with defective cell proliferation and survival [9], [10], [28]. In Smad4 CKO embryos, we also detected less proliferative ureteral mesenchymal cells with apoptosis at E14.5.…”

“…Although a few genes (e.g., Tbx18 , Sox9 , Tszh3 and β-catenin ) have been identified crucial for ureter development [2], [7]–[9], the interaction network of these genes with other factors in regulating ureteral SMC development remains to be determined. In this study, we found loss of Smad4 in the ureteral mesenchyme led to failure of SMC differentiation, resulting in severe hydroureter and hydronephrosis during mouse embryogenesis.…”