Forming nephrons promote nephron progenitor maintenance and branching morphogenesis via paracrine BMP4 signalling under the control ofWnt4

Abstract

Kidney development is known to be driven by interactions between stromal, nephron and ureteric epithelium progenitors in the nephrogenic niche. In contrast, the epithelial nephrons generated in this environment have largely been considered a product of niche rather than an active participant in the signalling interactions that maintain it. However, knockout ofWnt4, a gene required for nephron formation and stromal development, results in hypoplastic kidneys. We hypothesised that the forming nephron may play a role in maintaining the nephrogenic niche. In support of this hypothesis, conditional deletion ofWnt4from the nephron lineage resulted in nephron progenitor dispersal and death, reduced branching morphogenesis and nephron progenitor cell number. Bulk and single cell transcriptional profiling ofWnt4mutant kidneys revealed a downregulation of BMP signalling effectorsId1,and Id3in nephron progenitor cells, implicatingWnt4target BMP4 as a paracrine signal mediating feedback from the committing nephron. Recombinant BMP4 restored nephron progenitor compaction in culturedWnt4mutant kidneys and blocked differentiation in wildtype controls mirroring the role of BMP7-MAPK signalling in progenitor self-renewal. Our data supports a revised model of the nephrogenic niche in which forming nephrons promote progenitor maintenance and branching morphogenesis, in part via paracrine BMP4 signalling under the control ofWnt4. This requirement for nephron-derived signals for maintenance of the nephrogenic niche provides new mechanistic insight into kidney morphogenesis and human renal hypodysplasia phenotypes associated with deleteriousWNT4mutations.