We are interested in understanding the cellular and molecular basis of pediatric genetic disorders of the kidney. Specifically, we study the molecular regulators of tubule morphogenesis and cell fate specification in mouse models of congenital cystic kidney disease and collecting duct disorders, with the intent of finding better therapies for these diseases.
The cellular and molecular basis of congenital cystic kidney diseases.
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. In a second approach, we are developing cell culture assays in which to perform unbiased screens to identify genes that regulate the orientation of cell division plane and those that coordinate cilia turnover with cell cycle. Since genes that regulate cilia turnover and mitotic spindle orientation are also known to regulate tubular diameter and behave as tumor suppressors, these approaches should result in the identification of potentially novel epithelial cyst and tumor suppressor genes.
Figure 1: A cell culture system we are utilizing to identify the molecular regulators that maintain epithelia as a monolayer within a tubular structure results in the formation of spherical structures having a centrally located lumen when normal renal epithelial cells are grown in collagen matrix.
The signaling pathways that regulate the differentiation of kidney collecting duct epithelial cell types critical for water, electrolyte and pH homeostasis.
Another area of interest is to understand how cell fates are specified. Specifically, we are determining how the intermingled cell types of the renal collecting duct are specified and maintained, since very little is known about the differentiation of these epithelia which contribute to water, electrolyte and pH homeostasis. The two main cell types of the collecting duct reside intermingled along the entire collecting duct system (Figure 2), with a gradual increase in ratio of principal to intercalated cell types toward the medulla. These cell types arise from a common progenitor, but precise cell lineage relationships and molecular mechanisms patterning the collecting duct cell fates are mostly unknown. The intercalated and principal cell ratio may adapt to physiologic stress, but whether this involves a simple expansion of a cell type, trans-differentiation, or requires reserve multi-potent precursors to undergo differentiation is unclear. We are currently examining the roles of signaling pathways, such as Notch, TGFb/BMP and Wnt, in the process by which precursors of the collecting duct cell types differentiate into principal and intercalated cell types. These studies will provide insights into the molecular basis of physiologic disorders of collecting duct origin, such as nephrogenic diabetes insipidus and renal tubular acidosis, and will reveal general principles by which Notch, Wnt and TGFb/BMP pathways specify and maintain cell identities.
Figure 2: The principal and intercalated cells reside next to each other in the collecting ducts of normal mouse kidneys. We have generated mutant mice that have increased number of intercalated cells and reduced principal cells resulting in abnormal kidney function.
Contact Information for Surendran Lab:
Kamesh Surendran, PhD
Associate Scientist, Sanford Children's Health Research Center