Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy

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Abstract
Canonical Wnt signaling is known to be crucial in embryonic organ development. Joseph Gleeson and his colleagues now report that it is also important in the adult homeostasis of the kidney, especially after injury, and that disruption of this signaling pathway results in cystic kidney disease. Cystic kidney disease represents a major cause of end-stage renal disease, yet the molecular mechanisms of pathogenesis remain largely unclear. Recent emphasis has been placed on a potential role for canonical Wnt signaling, but investigation of this pathway in adult renal homeostasis is lacking. Here we provide evidence of a previously unidentified canonical Wnt activity in adult mammalian kidney homeostasis, the loss of which leads to cystic kidney disease. Loss of the Jouberin (Jbn) protein in mouse leads to the cystic kidney disease nephronophthisis, owing to an unexpected decrease in endogenous Wnt activity. Jbn interacts with and facilitates β-catenin nuclear accumulation, resulting in positive modulation of downstream transcription. Finally, we show that Jbn is required in vivo for a Wnt response to injury and renal tubule repair, the absence of which triggers cystogenesis.