Cathy Lee Mendelsohn, PhD
Dr. Mendelsohn obtained a BS in Microbiology from the University of Massachusetts at Amherst. She obtained a PhD in Microbiology at Columbia University Medical Center, working in Dr. Vincent Racaniello's lab where she cloned the human Poliovirus receptor. Her postdoctoral studies in Pierre Chambon's lab, at the UniversitÃ© Louis Pasteur, Strasbourg France were focused on Retinoic acid receptors and their role in development, studies which were continued in the lab of Jane Dodd at Columbia University looking at the role of retinoids in kidney development.
Project 1. Identification of progenitors important for Urothelial Development and Regeneration, and cells of origin for bladder cancer. The urothelium is a specialized barrier extending from the renal pelvis to the bladder neck that is critical for preventing exchange of water and toxic substances between the urinary tract and the blood. The urothelium is also a source of cells that generate different types of bladder cancers, including carcinoma in situ, papillary carcinoma, invasive cancers and squamous cell carcinoma. The urothelium is nearly quiescent but can rapidly regenerate in response to injury from toxic substances or urinary tract infection with Uropathogenic E.coli. The urothelium consists of 3 known cell types, Superficial cells, Intermediate cells and Basal cells. Superficial cells are specialized for synthesis and transport of uroplakins, a family of proteins that assemble into a tough crystalline barrier lining the urinary outflow tract. Superficial cells are binucleated and contain a DNA content of 8n. Our recent studies indicate that they are formed by failed cytokinesis, in which cells enter mitosis but failed to complete cytokinesis. Our studies further indicate that both binucleated Intermediate cells and Superficial cells can undergo endoreplication, entering S-phase to increase their DNA content without passing through mitosis. Intermediate cells are self-renewing Superficial cells during homeostasis and after acute injury, while after chronic injury accompanied by inflammation, the Intermediate cell population is depleted, and basal cells begin producing Intermediate cells, which produce Superficial cell daughters. Our current work on this project is aimed at identification of the genetic changes in basal cells that lead to increased regenerative capacity.
Project 2. Characterization transcriptional signaling pathways that regulate urothelial development and regeneration. Our previous studies identified retinoids as critical regulators of urothelial development and regeneration. We find that retinoids, which are secreted by stromal cells, activate Retinoic acid receptors (Rars) expressed in P-cells, a stem cell population that produces both Intermediate and Basal cells. We find that retinoid signaling is high between E11 and E13, when P-cells generate Intermediate cell daughters, and is down-regulated after E14, when P-cells give rise to basal cells. We showed using a dominant negative allele of Rar (Rosa26R;RaraDN) to block RA-signaling in the developing urothelium, that impaired retinoic acid signaling prevents P-cells from producing Intermediate cells and promotes formation of an abnormal squamous population of basal cells (Krt14+/K5+) cells. Expression of the dominant negative RA-receptor in the adult urothelium impairs urothelial regeneration and results in squamous metaplasia, in which the urothelium is replaced by a keratinized squamous epithelium resembling skin, which is likely to be derived from endogenous basal cells.
Project 4. Generating an atlas of cell types in the mouse and human urothelium. As part of the Genitourinary Tract Development Molecular Anatomy Consortium (http://www.gudmap.com/) we are generating expression profiles of urothelial cell types from the mouse and human as well as adjacent stroma during development, and in adults. Data is being collected using a combination of bulk RNAseq and scRNAseq, which will be validated and uploaded onto the GUDMAP and GEO websites, available to the public. The goal of these studies is producing a "map" of the distribution of stromal-epithelial signaling pathways that control development and patterning in the lower urinary tract.
Project 3: Role of Pparg in urothelial development, homeostasis and in bladder cancer. Expression profiling of RaraDN mutants during development revealed that Pparg, a member of the nuclear receptor superfamily, was down-regulated. Pparg is a critical regulator of lipid metabolism, and Pparg mutations are associated with bladder cancer. Analysis of Pparg mutants during development and in adults reveals a number of phenotypes that are also present in Rar mutants. We find that Pparg mutants fail to produce Intermediate cells during development, and instead produce basal cells (K14+/K5+), and during adulthood, Pparg is required in basal cells, for suppressing squamous differentiation and for maturation and survival of Superficial cells. These observations suggest that Pparg may act downstream of retinoids in the urothelium during development, and in adults. Current projects are focused on generating RNAseq expression data and chip-seq data to identify transcriptional targets of Pparg in the urothelium.
Work from the TCGA and other groups identifies gain of function and loss of function Pparg mutations in bladder cancer lesions of the luminal and basal subtype, respectively. We have generated GOF and LOF mouse models to examine the effects of these mutations in the adult urothelium. These animals will serve as models for investigating the molecular changes and cellular behavior during tumor formation which will be validated in bladder cancer lesions from human patients.
Project 5. The genetic origins and complications of urinary tract abnormalities. Columbia University George M. O’brien Urology Research Center (http://cumcobriencenter.com). Co-PIs: Cathy Mendelsohn, PhD, Jonathan Barasch, MD PHD, Ali Gharavi, MD. Urinary Tract Obstruction is a collection of abnormalities including Posterior urethral valves, Vesicoureteral reflux and Hydronephrosis that are common birth defects in humans accounting for 20% chronic kidney failure in children. The Columbia University O’Brien Urology Center is a NIH funded project that brings together research programs in Human Genetics and Mouse models to address the causes of congenital urinary tract malformations. Our Center consists of 3 research projects and an administrative core. The scientific aims of our research projects are highly interconnected, focused on identifying the genetic and embryological causes of obstruction and the related events that lead to renal disease. The Administrative Core of the center is focused on promoting vigorous exchange of ideas, data sharing between projects and with other researchers in the field of benign urology. We will accomplish these goals by providing research opportunities for students and fellows, providing research opportunities to under-represented minorities.
PubMed Id: 25968320. Authors: Georgas KM Armstrong J Keast JR Larkins CE McHugh KM Southard-Smith EM Cohn MJ Batourina E Dan H Schneider K Buehler DP Wiese CB Brennan J Davies JA Harding SD Baldock RA Little MH Vezina CM Mendelsohn C
PubMed Id: 26501074. Authors: Wu XR Mendelsohn C DeGraff DJ
PubMed Id: 25218638. Authors: Van Batavia J Yamany T Molotkov A Dan H Mansukhani M Batourina E Schneider K Oyon D Dunlop M Wu XR Cordon-Cardo C Mendelsohn C
PubMed Id: 24752063. Authors: Yamany T Van Batavia J Mendelsohn C
PubMed Id: 23993789. Authors: Gandhi D Molotkov A Batourina E Schneider K Dan H Reiley M Laufer E Metzger D Liang F Liao Y Sun TT Aronow B Rosen R Mauney J Adam R Rosselot C Van Batavia J McMahon A McMahon J Guo JJ Mendelsohn C