Kidney cysts occur following inactivation of polycystins in otherwise intact cilia or following complete removal of cilia by inactivation of intraflagellar transport-related proteins. We investigated the mechanisms of cyst formation in these two distinct processes by combining conditional inactivation of polycystins with concomitant ablation of cilia in developing and adult kidney and liver. We found that loss of intact cilia suppressed cyst growth following inactivation of polycystins and that the severity of cystic disease was directly related to the length of time between the initial loss of the polycystin proteins and the subsequent involution of cilia. This cilia-dependent cyst growth was not explained by activation of the MAPK/ERK, mTOR or cAMP pathways and is likely to be distinct from the mechanism of cyst growth following complete loss of cilia. These data establish the existence of a new pathway defined by polycystin-dependent inhibition and cilia-dependent activation that promotes rapid cyst growth.
Bibliographical noteFunding Information:
We are grateful to D. Shao and S.A. Mentone for assistance with tissue histology, K. Anderson and T. Caspary (Memorial Sloan-Kettering) for the antibody to Arl13b, P. Aronson (Yale University) for forskolin, E. Brown (University of Pennsylvania) for UBC-creER transgenic mice, L. Goldstein (University of California, San Diego) for Kif3afl mice, the Yale Mouse Metabolic Phenotyping Center for serum urea nitrogen measurement, Core resources from the Yale O’Brien Kidney Center (NIH/NIDDK P30 DK079310) for support with BAC transgenic lines and the Center for Polycystic Kidney Disease Research at Yale (NIH/NIDDK P30 DK090744) for mouse lines. We thank Y. Cai, S. Fedeles, R. Gallagher, Z. Yu and X. Cong for helpful discussions. This work was supported by US National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) grants R01 DK54053, RC1 DK086738 and R01 DK51041 (S.S.).