Transcription factors AP-2α and AP-2β regulate distinct segments of the distal nephron in the mammalian kidney

Transcription factors AP-2 alpha and AP-2 beta have been suggested to regulate the differentiation of nephron precursor populations towards distal nephron segments. Here, we show that in the adult mammalian kidney AP-2 alpha is found in medullary collecting ducts, whereas AP-2 beta is found in distal nephron segments except for medullary collecting ducts. Inactivation of AP-2 alpha in nephron progenitor cells does not affect mammalian nephrogenesis, whereas its inactivation in collecting ducts leads to defects in medullary collecting ducts in the adult. Heterozygosity for AP-2 beta in nephron progenitor cells leads to progressive distal convoluted tubule abnormalities and beta-catenin/mTOR hyperactivation that is associated with renal fibrosis and cysts. Complete loss of AP-2 beta in nephron progenitor cells caused an absence of distal convoluted tubules, renal cysts, and fibrosis with beta-catenin/mTOR hyperactivation, and early postnatal death. Thus, AP-2 alpha and AP-2 beta have non-redundant distinct spatiotemporal functions in separate segments of the distal nephron in the mammalian kidney. How the distal nephron is patterned during kidney development has been difficult to study. Here they show that AP-2 beta is required for the formation and postnatal function of distal convoluted tubules, whereas AP-2 alpha has a role in maintaining the structure of medullary collecting ducts.