Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. This model broadly applies to the nephrogenic niche of the developing mouse kidney where spatially restricted signals within the tips of the ureteric epithelium are thought to pattern coarse subdomains in surrounding clouds of mesenchymal nephron progenitor cells. These subdomains are assumed to reflect a linear progression in fate from an uninduced nephron progenitor state, through progressive stages of commitment, to an early epithelial nephron. While this is the dominant model in the field, our previous work identified a substantial amount of cell movement within and between nephron progenitor niches, including large cell movements from the ‘uninduced’ region to the site of nephron commitment and vice versa. As such, our results of a swarming nephron progenitor population were at odds with the current linear, domain-based model of nephron progenitor regulation.
How then does progenitor cell migration impact on regionally induced commitment within the nephrogenic niche? Using lineage tracing and live imaging we identify a subset of cells that are induced to express Wnt4, an early marker of nephron commitment, but migrate back into the progenitor population where they accumulate over time. Single cell RNA-Seq and computational modelling of returning cells reveals that nephron progenitors can traverse the transcriptional hierarchy between self-renewal and commitment in either direction. Our observation of cells which receive a trigger to initiate Wnt4 expression but fail to commit may indicate a requirement for prolonged induction or a second, as yet undefined, consolidating trigger. These results demonstrate that nephron progenitor commitment is a stochastic process influenced by cell migration, which regulates exposure to local inductive cues. The demonstrated plasticity in nephron progenitor fate may enable robust regulation of nephron formation as niches remodel and grow during kidney development.