Tailbud-derived mesenchyme promotes urinary tract segmentation via BMP4 signaling

Abstract

*Urinary tract morphogenesis requires the sub-division of the ureteric bud (UB) into the intra-renal collecting system and ureter, two tissues with unique structural and functional properties. In this report we investigate the cellular and molecular mechanisms that mediate their differentiation. Fate mapping experiments in the developing chick indicate that the UB is surrounded by two distinct mesenchymal populations: nephrogenic mesenchyme derived from the intermediate mesoderm and tailbud-derived mesoderm, which is selectively associated with the domain of the UB that differentiates into the ureter. Functional experiments utilizing murine metanephric kidney explants show that BMP4, a paracrine factor secreted by tailbud-derived mesenchyme, is required for ureter morphogenesis. Conversely, ectopic BMP4 signaling is sufficient to induce ureter morphogenesis in domains of the UB normally fated to differentiate into the intra-renal collecting system. Collectively, these results indicate that the border between the kidney and ureter forms where mesenchymal tissues originating in two different areas of the early embryo meet. These data raise the possibility that the susceptibility of this junction to congenital defects in humans, such as ureteral-pelvic obstructions, may be related to the complex morphogenetic movements that are required to integrate cells from these different lineages into a single functional structure.

Transcriptional profiling of the megabladder mouse: A unique model of bladder dysmorphogenesis

“…Bladder organogenesis is highly dependent upon the reciprocal interactions of embryonic endoderm and lateral plate mesoderm (Baskin et al, 1996;Staack et al, 2003). Embryonic endoderm gives rise to the bladder urothelium while the connective tissues and smooth muscle of the developing bladder are derived from the peri-cloacal mesenchyme (Haraguchi et al, 2007;Brenner-Anantharam et al, 2007). Genetic studies indicate the homeobox genes play an important role in determining the global patterning of the urogenital system (Satokata et al, 1995;Sciavolino et al, 1997;Warot et al, 1997;Goodman and Scambler, 2001;de Santa and Roberts, 2002;Troy et al, 2003), while key signaling molecules like sonic hedgehog and wnts have been implicated in determining the regional patterning within specific urogenital organs (Perriton et al, 2002;Freestone et al, 2003;Mericskay et al, 2004).…”

Absence of Canonical Smad Signaling in Ureteral and Bladder Mesenchyme Causes Ureteropelvic Junction Obstruction

“…Unlike the proximal ureter, the distal ureter is wrapped around by mesenchymal cells derived from the tail bud region. 5 The ureter provides a conduit for active transfer of urine from the kidney to the bladder propelled by peristalsis. Although the urothelium and the ureteral smooth muscle (SM) have distinct embryonic progenitors, they are tightly intertwined during development.…”

“…6 Bmp4 is also involved in the differentiation of mesenchymal cells into SM layers around the ureteral epithelium. 5 Apart from Bmp4, various other components of TGF-b superfamily are involved in nephrogenesis and the development of the urinary tract. [7][8][9][10] Signals from different TGF-b ligands and receptors diverge and converge on different sets of R-Smads (Smad2 and -3 for TGF-b, Activin, and Nodal and Smad1, -5, and -8 for Bmps), producing distinct and sometimes opposing outcomes.…”

Cell Biology of Ureter Development

“…It has, however, been postulated 45 that they may also result from perturbed intracellular signaling by analogy with the proven role for uroplakin proteins in triggering embryogenesis in frog eggs. UPK expression is compromised in ureters of mouse embryos engineered to have downregulated BMP4 51 or TBX18, 42 both proteins being normally expressed in adjacent SM precursor cells. Furthermore, application of BMP4 to explanted metanephroi induces UPK expression in ureteric bud branch tips within the organ, 51 suggesting that these UB descendants can be reprogrammed into a urothelial fate.…”

“…53 Peri-urothelial mesenchymal cells are also stimulated to express BMP4, which itself effects their own differentiation into SM. 51,53 Here, BMP4 enhances intracellular levels of phospho-SMADs 43,54 and upregulates TSHZ3, a transcription factor-like protein. TSHZ3 is needed for MYOCD expression within nascent ureteric SM cells.…”