Cilia dysfunction is a common factor underlying left-right axis malformation and the pathogenesis of virtually all known renal cystic diseases. Mutations in the RNA-binding protein Bicaudal-C (Bicc1) provoke cystic kidneys reminiscent of polycystic kidney disease (PKD), and ectopic Wnt/b-catenin signaling during left-right axis development. Renal cysts in these mice have been linked to defective miRNA-mediated silencing of specific mRNAs, including adenylate cyclase 6 (AC6) and protein kinase A inhibitor (PKIa), but little is known about how Bicc1 activities are regulated. Prompted by the overlapping phenotypes of mice lacking Bicc1 or Inversin (Invs), the protein defective in patients with nephronophthisis type II, we investigated a potential epistatic relationship. We found that Invs acts as an inhibitor of Bicc1 induced silencing and that Invs is required for Bicc1 localization to the Invs compartmentent in the proximal cilium. Molecular analysis demonstrated that Invs interacts with the Bicc1 KH domains required for mRNA binding. The Bicc1/Invs complex prevented the recruitment of target mRNA and their incorporation into miRNA-induced silencing complexes (miRISC). To test whether Bicc1 activity is regulated in vivo, we monitored Bicc1 targets in inv/inv mutant mouse kidneys lacking Invs. While AC6, the RNA helicase Ddx5 (a novel Bicc1 target) and PKA signaling were dramatically downregulated in inv/inv mutant kidneys, these effects were suppressed in Bicc1-/-; inv/inv double mutants, demonstrating that loss of Invs leads to ectopic activation of Bicc1. In autosomal dominant polycystic kidney disease (ADPKD), fluid-filled cysts develop in both kidneys due to defective calcium-permeable mechanosensory complexes of polycystin-1 and -2 encoded by PKD1 and PKD2. Studies in zebrafish suggest that Pkd2/Ca2+ signaling stimulates calmodulin kinase 2 (CaMK2). To further elucidate a role for Ca2+ in Bicc1 regulation, we mutated specific residues that are predicted to be phosphorylated by CaMK2. We found that CaMK2 phosphorylated Bicc1 on T724 and S805 and enabled miRISC assembly, at least in part by stimulating Bicc1 binding to nascent miRNAs. In addition, elevated Ca2+ concentrations prevented in vitro binding of Bicc1 to Invs. Based on these data we suggest a dual role for Ca2+ in regulating Bicc1. Elevated intracellular Ca2+ levels may induce the dissociation of a Bicc1/Invs complex and activate CaMK2 to enable Bicc1 mediated silencing of target mRNAs.