Temporal modulation of nephron progenitor competence orchestrates epithelial maturation during murine kidney development
July 9
Diverse nephron epithelial subtypes, encompassing proximal, distal and collecting duct lineages, emerge from multipotent progenitors within the metanephric mesenchyme. Using single-cell transcriptomics, chromatin-accessibility profiling, clonal lineage tracing, birth-dating, heterochronic transplantation and CRISPR-based perturbation sequencing in mouse embryos, we examined how temporal windows of progenitor competence govern epithelial maturation and differentiation. We found that the progression of nephrogenesis imposes a maturation-competence gradient on metanephric progenitors, dictating the rate at which their progeny acquire terminal epithelial features. By contrast, differentiation competence—defined as the ability to generate the full spectrum of nephron transcriptomic identities—remained preserved throughout organogenesis. Chromatin remodeling, together with a regulatory module centered on the transcription factor HNF1B and its downstream effectors, specifically regulated maturation competence in late-born epithelial cells. These findings reveal how temporal transcriptional programs and dynamic chromatin landscapes coordinate epithelial maturation and promote the diversification of nephron cell subtypes during kidney development.