Nephron and interstitial progenitor fates are plastic at the onset of mammalian kidney development

The kidney comprises the nephron parenchyma and the renal interstitium. Genetic fate mapping in mice indicates that Six2-expressing cap mesenchyme cells give rise to nephrons, whereas Foxd1-expressing cortical stromal cells give rise to the renal interstitium, suggesting a strict lineage boundary. However, the Six2-eGFPCre bacterial artificial chromosome (BAC) transgene used in these studies is activated after the onset of endogenous Six2 expression, leaving the earliest fate of Six2-expressing cells unresolved. Here, I show that a subset of Six2-expressing cells contributes to the renal interstitium at the onset of kidney development. A newly generated Six2-eGFPCre knockin allele faithfully recapitulates endogenous SIX2 expression without transcriptional delay and reveals this unexpected interstitial contribution. These findings indicate that early Six2-and Foxd1-expressing cells are not exclusively committed to the nephron and interstitial lineages, respectively, but retain alternative fate potential. Thus, lineage restriction is progressively established after nephrogenesis begins, ultimately enforcing a strict nephron-interstitium boundary.