SUMMARY: The distal nephron of the kidney has essential functions for urine concentration and electrolyte homeostasis. Defects in specific segments of the distal nephron can cause various kidney diseases, such as salt-losing tubulopathies that are characterized by an inability to concentrate urine. All nephrons are formed in the mouse by ~P3 postnatally, but the full functional capacity of the distal nephron is only achieved after a subsequent maturation phase, during which the distal nephron undergoes significant growth and functional changes. The maturation of the distal nephron has remained largely unstudied and it is not known which molecular and cellular mechanisms drive distal nephron maturation. Here, we will investigate the molecular mechanisms that orchestrate distal nephron maturation. We have identified the BTB-domain containing nuclear protein KCTD1, a transcriptional repressor, as an essential regulator of distal nephron maturation, for which a function in the kidney was previously unknown. We found KCTD1 to be expressed only in the distal nephron epithelium in the kidney and show that its deficiency impairs maturation and function of the thick ascending limb of Henle and the distal convoluted tubule, resulting in an early-onset salt-losing tubulopathy with a diminished ability to concentrate urine. The immature tubules undergo progressive dilatation and form enlarging cysts, changes leading to late-onset kidney fibrosis and renal failure. Inducible inactivation of KCTD1 during the distal nephron maturation phase leads to these distal tubule defects, but not when KCTD1 is inactivated in fully matured kidneys. Importantly, we identified missense mutations in KCTD1 in patients that develop kidney abnormalities resembling the findings in KCTD1 null mice, establishing the clinical relevance of KCTD1 for human kidney functions. Mechanistically, we show that loss of KCTD1 leads to postnatal derepression of the nuclear protein DAPL1 which precedes the manifestation of the distal nephron maturation defect and is associated with loss of the Wnt/planar cell polarity protein Dvl2 and increased canonical Wnt/β-catenin signaling. Furthermore, we show that DAPL1 regulates primary human distal nephron epithelial cell differentiation. Here, we will investigate the molecular mechanisms of how KCTD1 and DAPL1 regulate distal nephron maturation. Our proposed experiments are highly innovative and have significant clinical relevance, as they aim to uncover fundamental new mechanisms that are required for distal nephron maturation and which are impaired in several kidney disorders. Moreover, we will investigate how defects in distal nephron maturation affect late-onset chronic kidney disease-like pathologies and cystic kidney disease. The...