Abstract
Several Wnt proteins are expressed in the embryonic kidney during various stages of development. Gene knockout models and ex vivo studies have provided strong evidence that Wnt-mediated signals are essential in renal ontogeny. Perhaps the most critical factors, Wnt9b and Wnt4, function during the early phase when the cap mesenchyme is induced to undergo morphogenesis into a nephron. Wnt11 controls early ureteric bud branching and contributes to the final kidney size. In addition to its inductive role, later on Wnt9b plays a significant role in the convergent extension of the tubular epithelial cells, while Wnt4 signaling controls smooth muscle cell fates in the medulla. Wnt7b has a specific function together with its likely antagonist Dkk1 in controlling the morphogenesis of the renal medulla. The signal-transduction mechanisms of the Wnts in kidney ontogeny have not been resolved, but studies characterizing the downstream signaling pathways are emerging. Aberrant Wnt signaling may lead to kidney diseases ranging from fatal kidney agenesis to more benign phenotypes. Wnt-mediated signaling regulates several critical aspects of kidney development from the early inductive stages to later steps of tubular epithelial maturation.
Highlights
The definitive kidney of mammals, the metanephros, appears as a morphologically distinguishable rudiment around midgestation [1]
The early metanephros is composed of the epithelial ureteric bud (UB), an outgrowth from the adjacent Wolffian duct, and the metanephric mesenchyme (MM)
The MM is divided into the cap mesenchyme (CM), which is adjacent to the UB, and the cortical interstitial stroma, which surrounds the CM (Fig. 1)
Summary
The definitive kidney of mammals, the metanephros, appears as a morphologically distinguishable rudiment around midgestation [1]. Wnt9b-mediated induction in the CM initiates expression of Wnt, fibroblast growth factor 8 (Fgf8), paired box 8 (Pax8), and LIM homeobox protein 1 (Lhx1)-encoding genes [12, 16, 18,19,20] These genes fail to become expressed in the CM of Wnt9b-deficient embryonic kidneys and no nephrons form [16], as a result, Wnt9b knockout mice die soon after birth. In the case of Wnt deficiency, Pax and Fgf are initially expressed in few rudimentary pre-tubular aggregates [12, 20], which indicates that these factors function upstream of Wnt and downstream of Wnt9b (see above). Wnt acts in CM downstream of UBderived Wnt9b and is necessary for the formation of the pretubular aggregate and subsequent epithelial derivatives
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