The nephrons are the filtration units of the kidney that excrete toxins, balance salt and water content in the blood and regulate blood pressure. Their number is determined during kidney development by the size of the nephron progenitor cell (NPC) pool, which exhausts in early postnatal life in mouse. Understanding the mechanisms that regulate the balance between NPC self-renewal and differentiation is a crucial endeavour. In this issue, two papers provide insights into the molecular cues controlling NPC self-renewal.

On p. 1228, Zubaida Saifudeen and colleagues report that the specific deletion of p53 in mouse NPCs leads to hypoplastic kidneys, reduced nephron number and elevated blood pressure. p53 is classically associated with restraining proliferation, but the observed phenotype suggests a positive role for p53 in progenitor renewal: in mutants, NPC proliferation is reduced while senescence, apoptosis and the levels of known regulators of NPC survival remain unchanged. Furthermore, using functional genomics, the authors find that p53 regulates factors involved in cell-matrix interactions and metabolism. They then show that mutants display aberrant ATP and reactive oxygen species levels in NPCs. Altogether, these results uncover an unexpected contribution of p53 to NPC self-renewal capacity, energy metabolism and niche architecture.

In the second study (p. 1254), Martin Kann and co-workers identify growth arrest-specific 1 (Gas1) as a direct target of Wilms' tumor suppressor protein 1 (WT1), a transcription factor required for NPC self-renewal and differentiation. Phenotypically, the loss of GAS1 is similar to p53 depletion, with mutant mice displaying hypoplastic kidneys and decreased nephron numbers, stemming from reduced NPC proliferation. The authors further analyse the mechanism by which GAS1 acts in NPCs, finding that it modulates the response to fibroblast growth factor (FGF) signalling, a known regulator of NPC growth and proliferation, by specifically promoting the AKT pathway branch downstream of receptor activation. This study therefore links WT1 to FGF-mediated regulation of NPC proliferation, providing additional insights into the mechanisms by which this key transcription factor functions.