FGFR2 signaling enhances the SHH-BMP4 signaling axis in early ureter development

Abstract

The patterned array of basal, intermediate and superficial cells in the urothelium of the mature ureter arises from uncommitted epithelial progenitors of the distal ureteric bud. Urothelial development requires signaling input from surrounding mesenchymal cells, which, in turn, depend on cues from the epithelial primordium to form a layered fibro-muscular wall. Here, we have identified FGFR2 as a crucial component in this reciprocal signaling crosstalk in the murine ureter. Loss of Fgfr2 in the ureteric epithelium led to reduced proliferation, stratification, intermediate and basal cell differentiation in this tissue, and affected cell survival and smooth muscle cell differentiation in the surrounding mesenchyme. Loss of Fgfr2 impacted negatively on epithelial expression of Shh and its mesenchymal effector gene Bmp4. Activation of SHH or BMP4 signaling largely rescued the cellular defects of mutant ureters in explant cultures. Conversely, inhibition of SHH or BMP signaling in wild-type ureters recapitulated the mutant phenotype in a dose-dependent manner. Our study suggests that FGF signals from the mesenchyme enhance, via epithelial FGFR2, the SHH-BMP4 signaling axis to drive urothelial and mesenchymal development in the early ureter.

Upper Tract Urinary Carcinoma: A Unique Immuno-Molecular Entity and a Clinical Challenge in the Current Therapeutic Scenario

“…16 SHH-FOXF1-BMP4 axis controls epithelial differentiation, survival, proliferation and smooth muscle cell differentiation of the surrounding mesenchymal cells. 15 PAX2, PAX8, GATA3, and RET genes appear to be implicated in the regulation of ND morphogenesis. 12,17,18…”

“…To date, 3 classes of secreted proteins are known to be responsible for mesenchymal signals for urothelial development: bone morphogenetic protein 4 (BMP4), retinoic acid (RA), and fibroblast growth factors (FGFs). 15 Forkhead Box F1 (FOXF1) regulates the expression of BMP4 in the ureteric mesenchyme and is, in turn, regulated by the epithelial sonic hedgehog (SHH) signal, whose gene is expressed in the cloaca epithelia. 16 SHH-FOXF1-BMP4 axis controls epithelial differentiation, survival, proliferation and smooth muscle cell differentiation of the surrounding mesenchymal cells.…”

“…16 SHH-FOXF1-BMP4 axis controls epithelial differentiation, survival, proliferation and smooth muscle cell differentiation of the surrounding mesenchymal cells. 15 PAX2, PAX8, GATA3, and RET genes appear to be implicated in the regulation of ND morphogenesis. 12,17,18 In the view of this complex and multifaceted embryogenetic process, urothelial umbrella cells of the human ureter significantly differ from bladder cells in their uroplakin content, keratin expression pattern, and extracellular matrix-associated proteins.…”

Turning gray selenium and sublimed sulfur into a nanocomposite to accelerate tissue regeneration by isothermal recrystallization

“…In addition, Nano-Se@S (Fig. 5 C) and Nano-Se jointly regulate the FGF signalling pathway, which is conducive to promoting cell proliferation and migration during tissue regeneration [ 42 ]. These results suggest that Nano-Se@S may reduce the inflammatory reaction and promote biosynthesis to facilitate tissue regeneration.…”

Deficiency of Pdcd10 causes urothelium hypertrophy and vesicle trafficking defects in ureter

“…To date, several transcriptional regulators and signaling pathways have been reported to regulate the development of ureter and the ureteral urothelium, including FGF, SHH, BMP4, BRG1, PPARc, etc. [3,[17][18][19][20][21]. Recently, it has been reported that Pdcd10 in combination with the GCKIII subfamily of kinases, including Stk24 and Stk25, play a role in water homeostasis within mammalian kidney [22].…”