Going in circles: conserved mechanisms control radial patterning in the urinary and digestive tracts

Abstract

Radial patterning in the urinary tract and gut depends on reciprocal signaling between epithelial cells, which form mucosa, and mesenchyme, which forms smooth muscle and connective tissue. These interactions depend on sonic hedgehog (Shh), which is secreted by epithelial cells and induces expression of bone morphogenetic protein 4 (Bmp4), a signaling molecule required for differentiation of smooth muscle progenitors. Patterning of the specialized mucosa lining the anterior-posterior (A-P) axis may be controlled independently by regionally expressed mesenchymal transcription factors. A study by Airik et al. in this issue of the JCI reveals that T-box 18 (Tbx18), a transcription factor selectively expressed in ureteral mesenchyme, regulates smooth muscle differentiation by maintaining Shh1 responsiveness in mesenchymal progenitors (see the related article beginning on page 663). Deletion of Tbx18 resulted in defective urothelial differentiation at the level of the ureter, suggesting that Tbx18 acts via mesenchyme as an important regulator of A-P patterning in the urinary tract.

Figure 1

The embryonic urinary tract. (A and B) Schematic representations of the mouse urinary tract at E11.5 (A) and E15 (B). (C) Whole-mount urinary tract from an E15 mouse stained with uroplakin (red), a marker of the urothelium, and α-SMA (green), a marker of smooth muscle. The A-P and radial axes are shown with white arrows. Note that urothelial differentiation occurs in renal pelvis, ureters, and bladder, but not in the kidney, which is lined with a distinct mucosa. Magnification, ×10.

Figure 2

A model of Tbx18 action in radial patterning and urothelial differentiation. (A) Tbx18 is selectively expressed in ureteral mesenchyme, where it is required for smooth muscle differentiation and for differentiation of the urothelium, the specialized mucosa that provides barrier function. Tbx18 controls smooth muscle differentiation by regulating Shh responsiveness in subepithelial mesenchyme (3). Shh secreted from ureteral epithelia induces expression of Patched1 and Bmp4, a signaling molecule critical for recruitment of ureteral mesenchyme and for its differentiation into smooth muscle. (B) Tbx18 is selectively expressed in ureteral mesenchyme and is important for differentiation of the urothelium lining the ureters, but not the urothelium lining the bladder and urethra.