Hwang, S.-H.; Choi, K.; Badgandi, H.; White, K.; Xun, Y.; Qian, F.; Mukhopadhyay, S.

Multiple cellular pathways are dysregulated in autosomal dominant polycystic kidney disease (ADPKD), but mechanisms initiating cyst formation are unknown. ADPKD is caused by mutations in Pkd1/Pkd2 genes that encode for polycystins that localize to primary cilia. The primary cilium is a miniscule subcellular compartment for generating signaling outputs that profoundly affect cellular function. Severe cystogenesis from polycystin loss is mostly cilia dependent. However, the polycystin-repressed ciliary signals that promote cyst growth are unknown and have been challenging to uncouple from downstream cystogenic pathways. Here we aimed at differentiating ciliary adenylyl cyclase signaling from total cellular changes in second messenger cAMP implicated in cystogenesis. We studied an Ankyrin repeat and MYND domain protein, ANKMY2 that we previously implicated in maturation and ciliary localization of adenylyl cyclases in fibroblasts. We studied kidney-specific conditional knockout mouse models of Ankmy2/Pkd1 and ciliary localization of adenylyl cyclases in kidney epithelial cells. We found suppression of early postnatal renal cystogenesis and prolonged survival in an embryonic onset Pkd1 deletion model from ANKMY2 loss. Phosphorylated CREB formation, from elevated cellular cAMP levels, remained unaffected. Cyst load in male mice in an adult inducible conditional Pkd1 deletion model was suppressed from ANKMY2 loss. Mechanistically, ANKMY2 determined ciliary trafficking of adenylyl cyclases in kidney epithelial cells without disrupting cilia. Further, ANKMY2 loss prevented ciliary length increase in ADPKD mouse models irrespective of cyst load or sex. Cilia length increase was seen preceding cystogenesis. Our results suggest that targeting of adenylyl cyclases to renal epithelial cilia promotes PC1/2-inhibited cilia-dependent cyst activation distinct from cyst progression involving cellular cAMP.