Identification of progenitors important for Urothelial Development and Regeneration, and cells of origin for bladder cancer
The urothelium is a specialized epithelium extending from the renal pelvis to the bladder that is critical for preventing exchange of water and toxic substances between the urinary tract and the blood. The urothelium is also thought to be a source of cells that generate different types of bladder cancers, including carcinoma in situ, papillary carcinoma, invasive cancers and squamous cell carcinoma.Projects:
-Using mouse models in fate mapping studies to identify progenitors that give rise to the urothelium during development and regeneration, coupled with RNAseq to identify signaling pathways that are normally important for these events.
-We showed recently that vitamin A (retinoic acid) is required in distinct progenitor populations for urothelial development and regeneration, respectively. To understand how retinoids work, we are sorting different urothelial cells from RA-mutants and controls then comparing their gene expression profiles using RNAseq.
-We are using mouse models of carcinogenesis coupled with fate mapping to identify cells of origin that give rise to papillary carcinoma, carcinoma in situ, squamous cell carcinoma and invasive bladder cancers. Developmental Studies to understand the etiology of urinary tract birth defects.
We are interested in the causes of hydronephrosis, a birth defect that in humans and mouse models is associated with severe kidney damage. Hydronephrosis can be caused by abnormally positioned distal ureters, which join the bladder outside the proper insertion site, or can be linked to bladder/urethral abnormalities such as urethral valves, a common defect found in newborn boys that results in urethral obstruction, bilateral hydronephrosis and renal damage. We are currently studying the cause of distal ureter abnormalities using Caspase knockout mice in which apoptosis, which is critical for proper insertion of ureter in the bladder is impaired.
Gandhi, D., Molotkov, A., Batourina, E., Schneider, K., Dan, H., Reiley, M., Laufer, E., Metzger, D., Liang, F., Liao, Y., Sun, T.T., Aronow, B., Rosen, R., Mauney, J., Adam, R., Rosselot, C., Van Batavia, J., McMahon, A., McMahon, J., Guo, J.J., and Mendelsohn, C
. (2013). Retinoid signaling in progenitors controls specification and regeneration of the urothelium. Dev Cell
Paroly, S., Wang, F., Spraggon, L., Merregaert, J., Batourina, E., Schmidt-Ott, K., Grimmond, S., Little, M., and Mendelsohn, C
. (2013). Stromal protein Ecm1 regulates ureteric bud patterning and nephron differentiation. Plos1 In press
Chia, I., Grote, D., Marcotte, M., Batourina, E., Mendelsohn, C
., and Bouchard, M. (2011). Nephric duct insertion is a crucial step in urinary tract maturation that is regulated by a Gata3-Raldh2-Ret molecular network in mice. Development
Rosselot, C., Spraggon, L., Chia, I., Batourina, E., Riccio, P., Lu, B., Niederreither, K., Dolle, P., Duester, G., Chambon, P., Costantini, F., Gilbert, T., Molotkov, A., and Mendelsohn, C
. (2010). Non-cell-autonomous retinoid signaling is crucial for renal development. Development
Chi, X., Michos, O., Shakya, R., Riccio, P., Enomoto, H., Licht, J.D., Asai, N., Takahashi, M., Ohgami, N., Kato, M., Mendelsohn, C
., and Costantini, F. (2009). Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell
Viana, R., Batourina, E., Huang, H., Dressler, G.R., Kobayashi, A., Behringer, R.R., Shapiro, E., Hensle, T., Lambert, S., and Mendelsohn, C
. (2007). The development of the bladder trigone, the center of the anti-reflux mechanism. Development
Schmidt-Ott, K.M., Chen, X., Paragas, N., Levinson, R.S., Mendelsohn, C.L.
, and Barasch, J. (2006). c-kit delineates a distinct domain of progenitors in the developing kidney. Dev Biol
Batourina, E., Tsai, S., Lambert, S., Sprenkle, P., Viana, R., Dutta, S., Hensle, T., Wang, F., Niederreither, K., McMahon, A.P., Carroll, T.J., and Mendelsohn, C.L.
(2005). Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder. Nat Genet
Batourina, E., Choi, C., Paragas, N., Bello, N., Hensle, T., Costantini, F.D., Schuchardt, A., Bacallao, R.L., and Mendelsohn, C.L.
(2002). Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet
Batourina, E., Gim, S., Bello, N., Shy, M., Clagett-Dame, M., Srinivas, S., Costantini, F., and Mendelsohn, C
. (2001). Vitamin A controls epithelial/mesenchymal interactions through Ret expression. Nat Genet