New roles of Bicc1 in cilia formation, cell adhesion, and in adult kidneys.

Bicaudal-C1 (Bicc1), an RNA-Binding protein, is a ciliopathy-associated protein. In development, Bicc1 is necessary for left-right axis specification. Loss of Bicc1 in mice also associates with polycystic kidney development. In human, two hereditary polycystic kidney diseases (PKD) exist, autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease. Since there exists no cure, both frequently lead to end-stage renal disease. Bicc1 was shown to be important for motile cilia positioning and function at the node of embryos. In addition, Bicc1 interacts with known ciliary proteins and functions in flow sensing by immotile cilia. Bicc1 regulates cyclic adenosine monophosphate (cAMP)/ protein kinase A (PKA) signaling by repressing adenylyl cyclase 6 (AC6) mRNA translation. How Bicc1 is regulated by flow stimulation of cilia is still not understood. Here, imaging of primary cilia in CRISPR-edited IMCD3 cell lines lacking the main form of Bicc1 revealed an unexpected new role to allow cilia assembly or stability. I found that in the absence of full-length Bicc1, a hitherto unknown shorter isoform arising from an alternative initiation site in exon 1 blocked ciliogenesis. Using immunofluorescence stainings, transient localisation of Bicc1 to the centrosome and peri-centriolar satellites was validated and shown to be tightly regulated by serum starvation and by at least two Bicc1-interacting factors, including the ankyrin repeat and sterile α motif domain containing 3 (Anks3) protein, and the NIMA-related kinase Nek7. The loss of cilia in cells expressing only short Bicc1 was associated with the repression of Rho-Associated protein kinase (ROCK). We showed that inhibition of ROCK signaling by full-length Bicc1 is important both for cilia lengthening and for cell adhesion. Moreover, by introducing conditional kidney-specific Bicc1 knock-out mice, I found that Bicc1 is also required in adult mice to inhibit cyst formation, and that it functions not only in proximal tubules, but also in distal segments. Analysis of mice deleted of Bicc1 specifically in the kidney will help us to understand the role of Bicc1 in different segments of renal tubules.