MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.

Healy, Marc E; Boege, Yannick; Hodder, Michael C; Böhm, Friederike; Malehmir, Mohsen; Scherr, Anna-Lena; Jetzer, Jasna; Chan, Lap Kwan; Parrotta, Rossella; Jacob, Kurt; Clerbaux, Laure-Alix; Kreutzer, Susanne; Campbell, Andrew; Gilchrist, Ella; Gilroy, Kathryn; Rodewald, Ann-Katrin; Honcharova-Biletska, Hanna; Schimmer, Roman; Vélez, Karelia; Büeler, Simone; ... (2020). MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice. Gastroenterology, 159(1), pp. 183-199. Elsevier 10.1053/j.gastro.2020.03.017

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BACKGROUND & AIMS

Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. Disruption of factors that promote IEC death result in intestinal inflammation, whereas loss of antiapoptotic proteins, such as BCL2 or its family member BCL2L1, has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice.

METHODS

We generated mice with IEC-specific disruption of Mcl1 (Mcl1ΔIEC mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i-Mcl1ΔIEC mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Some mice were given antibiotics in their drinking water or the PORCUPINE WNT inhibitor WNT974. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces.

RESULTS

Mcl1ΔIEC mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1ΔIEC mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1ΔIEC mice reduced markers of microbiota-induced intestinal inflammation but not tumor development.

CONCLUSION

The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1ΔIEC mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Gastroenterologie / Mukosale Immunologie

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery

UniBE Contributor:

Wenning, Anna Silvia; McCoy, Kathleen; Gomez de Agüero Tamargo, Maria de la Mercedes and Macpherson, Andrew

ISSN:

0016-5085

Publisher:

Elsevier

Language:

English

Submitter:

Professor Andrew Macpherson

Date Deposited:

24 Jun 2020 11:09

Last Modified:

16 Dec 2020 12:08

Publisher DOI:

10.1053/j.gastro.2020.03.017

PubMed ID:

32179094

Uncontrolled Keywords:

CRC Cell Death Colorectal Carcinoma Tumorigenesis

BORIS DOI:

10.7892/boris.144822

URI:

https://boris.unibe.ch/id/eprint/144822

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