Plumbing in the embryo: developmental defects of the urinary tracts

Abstract

Kidney and urinary tract malformations are among the most frequent developmental defects identified in newborns. Ranging from asymptomatic to neonatal lethal, these malformations represent an important clinical challenge. Recent progress in understanding the developmental origin of urinary tract defects in the mouse and other animal models suggests a new framework for the interpretation of these defects in humans. Gene inactivation studies in mice provided invaluable information on the formation of the Wolffian duct, a central component of embryonic renal development, on ureter and kidney induction as well as on distal ureter maturation. All three developmental processes are crucial for normal urinary tract morphogenesis. A failure to complete these developmental steps is responsible for a spectrum of kidney and urinary tract malformations including renal agenesis, renal dysplasia, vesicoureteral reflux, hydroureter, hydronephrosis and ureterocele. Surprisingly, distal ureter maturation, the process by which the ureter is displaced from the Wolffian duct to its final position within the bladder wall, has only recently been characterized at the morphological level. Anomalies in this process are emerging as a major source of urinary tract developmental defects. This review is aimed at bridging the current knowledge on the morphological and molecular events identified in the mouse, together with clinical observations of urinary tract malformation in humans.

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

“…Despite its simple design and the relevance of congenital defects of the ureteric wall, only a small number of genes crucial for development of the ureteric mesenchyme have been characterized in recent years (Airik and Kispert, 2007;Uetani and Bouchard, 2009). Phenotypic analyses of mutant mice suggested that the Tbox transcription factor gene 18 (Tbx18) specifies the ureteric mesenchyme (Airik et al, 2006); that Bmp4, a member of the family of secreted bone morphogenetic proteins, inhibits budding and branching morphogenesis of the distal ureteric epithelium, directs a ureteric fate and/or promotes SMC differentiation (Brenner-Anantharam et al, 2007;Dunn et al, 1997;Miyazaki et al, 2003); that the transcriptional regulators GATA binding protein 2 (Gata2), teashirt zinc finger family member 3 (Tshz3) and SRYbox containing gene 9 (Sox9) act as downstream mediators of Bmp4 function in the mesenchyme to activate expression of myocardin (Myocd), the key regulator of SMC differentiation Caubit et al, 2008;Wang and Olson, 2004;Zhou et al, 1998); and that sonic hedgehog (Shh) signaling from the ureteric epithelium maintains Bmp4 in the mesenchyme and dose-dependently inhibits SMC fates (Yu et al, 2002).…”

Urinary Tract Anomalies Associated with MTHFR Gene Polymorphism C677T in Girls

“…The second major process is urogenital sinus (cloaca) development from endodermal cells, forming a definite urinary bladder, ureter-bladder connection and urethra (gene regulation, e.g. by Aldh1a2, PTPRF, PTPRS, NFIa, L1-CAM and others) [40][41][42] . The UT is also developmentally linked with the genitals, mostly through key Müllerian and Wolffian duct regulators [35] .…”

GDNF/Ret signaling and renal branching morphogenesis

“…The correct rostral-caudal positioning of the UB is very important, as buds that form in the wrong position results in a ureter that fails to connect correctly to the bladder. 4 After the UB penetrates the metanephric mesenchyme (E11.0), it begins to branch repeatedly, mostly by bifurcation at the tips. 5 Other modes of branching (lateral budding and terminal trifurcation) also occur less frequently, at least in organ culture; 5 the patterns of branching that occur in vivo have not been well documented in the mouse kidney, as they have been in the lung.…”