One of the central questions in the laboratory is how renal tubules establish their size and diameter and how this process is perturbed during Polycystic Kidney Disease (PKD). This disease is characterized by the uncontrolled expansion of renal tubules resulting in the formation of numerous fluid-filled cysts and massively enlarged kidneys. In humans, PKD is one of the most common diseases caused by a mutation in a single gene. It is the leading cause of end-stage renal failure in the United States and the only existing treatment options are dialysis and kidney transplantation.
Our PKD research is centered on Bicaudal-C (Bicc1), an RNA-binding molecule first identified in Drosophila as a protein regulating anterior-posterior development. Mouse mutants of BicC1 develop kidney abnormalities reminiscent of Polycystic Kidney Disease. Molecular analyses demonstrate that Bicc1 acts as a post-transcriptional regulator of Polycystin-2, one of the genes mutated in human forms of PKD. It antagonizes the repressive activity of the miR-17 microRNA family on the 3’-UTR of Polycystin-2 mRNA. We postulate that the kidney phenotype in BicC1 mutant mice is caused by dysregulation of a microRNA-based translational control mechanism. It demonstrates - for the first time - that post-transcriptional regulation is important in maintaining epithelial structures and that the disruption thereof can result in disease formation.