Abstract
BackgroundDevelopment of the kidney is initiated when the ureteric bud (UB) branches from the Wolffian duct and invades the overlying metanephric mesenchyme (MM) triggering the mesenchymal/epithelial interactions that are the basis of organ formation. Multiple signaling pathways must be integrated to ensure proper timing and location of the ureteric bud formation.Methods and Principal FindingsWe have used gene targeting to create an Lrp4 null mouse line. The mutation results in early embryonic lethality with a subpenetrant phenotype of kidney agenesis. Ureteric budding is delayed with a failure to stimulate the metanephric mesenchyme in a timely manner, resulting in failure of cellular differentiation and resulting absence of kidney formation in the mouse as well as comparable malformations in humans with Cenani-Lenz syndrome.ConclusionLrp4 is a multi-functional receptor implicated in the regulation of several molecular pathways, including Wnt and Bmp signaling. Lrp4−/− mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis. These data indicate that Lrp4 is a critical regulator of UB branching and lack of Lrp4 results in congenital kidney malformations in humans and mice.
Highlights
The definitive kidney forms as a result of inductive interactions between the metanephric mesenchyme and the ureteric bud (UB) [1]
Lrp4 is a multi-functional receptor implicated in the regulation of several molecular pathways, including Wnt and Bmp signaling
Lrp42/2 mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis
Summary
The definitive kidney forms as a result of inductive interactions between the metanephric mesenchyme and the UB [1]. Signals from the metanephric mesenchyme stimulate the ureteric bud to branch from the Wolffian duct around embryonic stage E10.5 [2]. The timing and location of ureteric budding are critical factors in kidney organogenesis. Genetic and surgical manipulations have revealed that the mesenchyme is only competent to respond to signals from the bud for a narrow time window [4]. Failure of the bud to reach the mesenchyme in this narrow window results in apoptosis of the mesenchyme and subsequent kidney agenesis [5,6]. Development of the kidney is initiated when the ureteric bud (UB) branches from the Wolffian duct and invades the overlying metanephric mesenchyme (MM) triggering the mesenchymal/epithelial interactions that are the basis of organ formation. Multiple signaling pathways must be integrated to ensure proper timing and location of the ureteric bud formation
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