Wnt11 directs nephron progenitor polarity and motile behavior ultimately determining nephron endowment.

Lori L O'Brien,Luise A Cullen-Mcewen,Alexander N Combes,Odyssé Michos,Melissa H Little,Kieran M Short,Ahmed Abdelhalim,John F Bertram,Adler Ju,Andrew P Mcmahon,Ian M Smyth,Nils O Lindström,Peter H Whitney

doi:10.7554/elife.40392

Abstract

A normal endowment of nephrons in the mammalian kidney requires a balance of nephron progenitor self-renewal and differentiation throughout development. Here, we provide evidence for a novel action of ureteric branch tip-derived Wnt11 in progenitor cell organization and interactions within the nephrogenic niche, ultimately determining nephron endowment. In Wnt11 mutants, nephron progenitors dispersed from their restricted niche, intermixing with interstitial progenitors. Nephron progenitor differentiation was accelerated, kidneys were significantly smaller, and the nephron progenitor pool was prematurely exhausted, halving the final nephron count. Interestingly, RNA-seq revealed no significant differences in gene expression. Live imaging of nephron progenitors showed that in the absence of Wnt11 they lose stable attachments to the ureteric branch tips, continuously detaching and reattaching. Further, the polarized distribution of several markers within nephron progenitors is disrupted. Together these data highlight the importance of Wnt11 signaling in directing nephron progenitor behavior which determines a normal nephrogenic program.

Highlights

The developing mammalian kidney contains three distinct progenitor niches in the active nephrogenic zone
Wnt11 is required for nephron progenitor niche organization and proper nephron endowment
Previous reports suggested that branching morphogenesis is disrupted in Wnt11 mutants, leading to smaller kidneys (Majumdar et al, 2003)

Summary

Introduction

The developing mammalian kidney contains three distinct progenitor niches in the active nephrogenic zone. They consist of the mesenchymal nephron and interstitial progenitor cells and the epithelial ureteric progenitor cells (McMahon, 2016). The progenitor niches are self-renewing and give rise to the majority of cell types that make up the mature kidney (Kobayashi et al, 2008; Self et al, 2006; Kobayashi et al, 2014; Costantini, 2012). There is a distinct organization of these cell types within the nephrogenic niche. Nephron progenitors tightly cap ureteric branch tips throughout the arborization of the ureteric epithelial-derived collecting duct system, separating the ureteric branch.

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Conclusion