Abstract
Alagille syndrome patients present with loss of function mutations in either JAG1 or NOTCH2. About 40%-50% of patients have kidney abnormalities, and frequently display multicystic, dysplastic kidneys. Additionally, gain-of-function mutations in NOTCH2 are associated with cystic kidneys in Hajdu-Cheney syndrome patients. How perturbations in Notch signaling cause renal tubular cysts remains unclear. Here, we have determined that reduced Notch signaling mediated transcription by ectopic expression of dominant-negative mastermind-like (dnMaml) peptide in the nephrogenic epithelia from after the s-shaped body formation and in the developing collecting ducts results in proximal tubular and collecting duct cysts, respectively. An acute inhibition of Notch signaling for two days during kidney development is sufficient to disrupt tubule formation, and significantly increases Akap12 expression. Ectopic expression of Akap12 in renal epithelia results in abnormally long primary cilia similar to that observed in Notch-signaling-deficient epithelia. Both loss of Notch signaling and elevated Akap12 expression disrupt the ability of renal epithelial cells to form spherical structures with a single lumen when grown embedded in matrix. Interestingly, Akap12 can inhibit Notch signaling mediated transcription, which likely explains how both loss of Notch signaling and ectopic expression of Akap12 result in similar renal epithelial abnormalities. We conclude that Notch signaling regulates Akap12 expression while also ensuring normal primary cilia length and renal epithelial morphogenesis, and suggest that one aspect of diseases associated with defective Notch signaling, such as Alagille syndrome, maybe mechanistically related to ciliopathies.