https://phaidra.vetmeduni.ac.at/o:3031 Monogenic deficiency in murine intestinal Cdc42 leads to mucosal inflammation that induces crypt dysplasia Zhang, Dongsheng Dongsheng Zhang Case Western Reserve University / Cincinnati Children's Hospital Medical Center Han, Xiaonan Xiaonan Han Case Western Reserve University Zheng, Yi Yi Zheng Cincinnati Children's Hospital Medical Center Moriggl, Richard Richard Moriggl 0000-0003-0918-9463 Ludwig Boltzmann Institute for Cancer Research / University of Veterinary Medicine Vienna Kenner, Lukas Lukas Kenner 0000-0003-2184-1338 Medical University of Vienna Denson, Lee Lee Denson Cincinnati Children's Hospital Medical Center Song, Mingquan Mingquan Song Qingdao University Wang, Jiang Jiang Wang University of Cincinnati Themanns, Madeleine Madeleine Themanns University of Veterinary Medicine Vienna Karl-Heinz, Friedrich Friedrich Karl-Heinz University Hospital Jena Knösel, Thomas Thomas Knösel Ludwig-Maximilians-University Munich Dolznig, Helmut Helmut Dolznig Medical University of Vienna Tang, Wenjuan Wenjuan Tang Cincinnati Children's Hospital Medical Center / Children's Hospital of Fudan University Niu, Haitao Haitao Niu Jinan University / Chinese Academy of Medical Science and Peking Union Medical College Tse, William William Tse Case Western Reserve University Ruan, Hai-Bin Hai-Bin Ruan University of Minnesota Medical School KEAI Publishing Ltd text eng CDC42 controls intestinal epithelial (IEC) stem cell (IESC) division. How aberrant CDC42 initiates intestinal inflammation or neoplasia is unclear. We utilized models of inflammatory bowel diseases (IBD), colorectal cancer, aging, and IESC injury to determine the loss of intestinal Cdc42 upon inflammation and neoplasia. Intestinal specimens were collected to determine the levels of CDC42 in IBD or colorectal cancer. Cdc42 floxed mice were crossed with Villin-Cre, Villin-CreERT2 and/or Lgr5-eGFP-IRES-CreERT2, or Bmi1-CreERT2 mice to generate Cdc42 deficient mice. Irradiation, colitis, aging, and intestinal organoid were used to evaluate CDC42 upon mucosal inflammation, IESC/progenitor regenerative capacity, and IEC repair. Our studies revealed that increased CDC42 in colorectal cancer correlated with lower survival; in contrast, lower levels of CDC42 were found in the inflamed IBD colon. Colonic Cdc42 depletion significantly reduced Lgr5+ IESCs, increased progenitors' hyperplasia, and induced mucosal inflammation, which led to crypt dysplasia. Colonic Cdc42 depletion markedly enhanced irradiation- or chemical-induced colitis. Depletion or inhibition of Cdc42 reduced colonic Lgr5+ IESC regeneration. In conclusion, depletion of Cdc42 reduces the IESC regeneration and IEC repair, leading to prolonged mucosal inflammation. Constitutive monogenic loss of Cdc42 induces mucosal inflammation, which could result in intestinal neoplasia in the context of aging. Cre-Mediated Recombination; Stem-Cells; Colorectal-Cancer; Bowel-Disease; Human Colon; Survival; Differentiation; Proliferation; Tumorigenesis; Complex http://creativecommons.org/licenses/by-nc-nd/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:3031/download 10.1016/j.gendis.2022.11.024 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Genes & Diseases 11(1), 413-429 (2023) Genes & Diseases 11 1 413 429 1.13 MB 2023