Regulators of Renal tubule Morphogenesis
Mutations in several different genes have been linked to the pathogenesis of cystic kidney diseases in children. A common function of these genes is to regulate tubule morphogenesis. Hence, we wish to understand the molecular mechanisms that organize groups of cells into stereotypical tubular structures referred to as nephrons, the structural and functional units of the kidney. What regulates the length, and diameter of the various tubular segments of the nephron? What mechanisms regulate the epithelial cells of the nephron to remain as a monolayer during nephron growth, to ensure the correct thickness of the mature nephron? We have determined that the Notch signaling pathway regulates proximal nephron diameter and thickness to prevent the formation of tubular cysts and microadenomas, which may be precursors to papillary renal cell carcinoma. Interestingly, the mice we have generated with Notch signaling deficiency in the kidney, model the renal abnormalities known to occur in children with mutations in Notch2, including small kidneys with multiple cysts. Using these mouse models of congenital cystic kidney disease, we observed that Notch1 and Notch2 regulate the orientation of the epithelial cell division plane in order to maintain the epithelia in a monolayer as the proximal nephron grows.
Currently, we are determining the mechanisms by which Notch signaling suppresses cyst formation and regulates the orientation of epithelial cell division plane in order to uncover the cellular and molecular basis of cystic kidney diseases that originate during kidney development. We are taking both a biochemical and a genetic approach to determine how Notch signaling suppresses renal cyst formation. We are performing screens to identify genes regulated by Notch signaling and screens to identify proteins interacting with Notch receptors. For validating candidates we have developed cell culture assays and are performing live cell imaging to test candidate’s ability to regulate the orientation of cell division plane and to coordinate cilia turnover with cell cycle.