Department of Cellular and Molecular Medicine
Oliver Wessely, PhD
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-3050
Fax: (216) 444-9404
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.
In other words ...
Our research interests lie in the understanding of the molecular mechanisms governing kidney development. We are particularly intrigued by the complex cross talk that establishes the different cell types and the shape of the kidney and how these processes are perturbed during disease formation. In an approach to decoding this network we are currently focusing on identifying the key events or nodes of the network. Triggering those minimal inputs should allow us to initiate a self-organizing program that will continue the developmental program with little or no further intervention. To address these questions we are using a two-model organism approach studying the metanephric kidney of mouse and the pronephric kidney of Xenopus laevis. While mouse has been successfully used to study multiple aspects of kidney development, the amphibian pronephros of Xenopus offers a valuable alternative to explore the underlying molecular and cellular mechanisms. With its fast development (a functional pronephric kidney is formed by two days) and ease of molecular manipulations, it is an ideal companion system to the metanephric kidney. Using the distinct advantages of both organisms greatly facilitates the formulation and experimental testing of new hypotheses.
- Romaker D., Kumar V., Cerqueira D.M., Cox R.M., Wessely O. (2014) MicroRNAs are critical regulators of tuberous sclerosis complex and mTORC1 activity in the size control of the Xenopus kidney. Proc. Natl. Acad. Sci. USA. 111(17):6335-40
- Zhang B., Romaker D., Ferrell N., Wessely O. (2013) Regulation of G-Protein Signaling via Gnas is Required to Regulate Proximal Tubular Growth in the Xenopus Pronephros. Developmental Biology. Dev. Biol. 376(1), 31-42.
- Streets A., Wessely O., Peters D., Ong A. (2013) Hyperphosphorylation of Polycystin-2 at a Critical Residue in Disease Reveals an Essential Role in Polycystin-1 Mediated Dephosphorylation. Human Molecular Genetics. 22(10), 1924-1939.
- Wessely, O., and Tran, U. (2011). Xenopus pronephros development-past, present, and future. Pediatr. Nephrol. 26, 1545-1551.
- Tran, U., Zakin, L., Schweickert, A., Agrawal, R., Doger, R., Blum, M., De Robertis, E.M., and Wessely, O. (2010). The RNA-binding protein Bicaudal-C regulates Polycystin2 in the kidney by antagonizing miR-17 activity. Development 137, 1107-1116.
- White, J.T., Zhang, B., Cerqueira, D.M., Tran, U., and Wessely, O. (2010). Notch signaling, wt1 and foxc2 are key regulators of the podocyte gene regulatory network in Xenopus. Development 137, 1863-1873.
- Agrawal, R., Tran, U., and Wessely, O. (2009). The miR-30 miRNA family regulates Xenopus pronephros development and targets the transcription factor Xlim1/Lhx1. Development 136, 3927-3936.