Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2−/− mice

• Published in: Developmental biology Vol. 338; no. 2; pp. 270 - 279
• Main Authors: Zhao, Fang, Edwards, Robert, Dizon, Diana, Afrasiabi, Kambiz, Mastroianni, Jennifer R., Geyfman, Mikhail, Ouellette, André J., Andersen, Bogi, Lipkin, Steven M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-02-2010
• Subjects: AGR2, Anterior gradient 2; Animals; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; ER stress; Goblet cell; Goblet Cells - pathology; Homeostasis; Inflammatory Bowel Diseases - etiology; Intestine; Intestines - chemistry; Intestines - pathology; Mice; Mice, Knockout; Mucin-2 - analysis; Mucoproteins - deficiency; Mucoproteins - genetics; Paneth cell; Paneth Cells - pathology; PDI, protein disulfide isomerase; Stress, Physiological; Paneth cell; Goblet cell; PDI; AGR2, Anterior gradient 2; Intestine; AGR2; ER stress; ER; BrdU; PDI, protein disulfide isomerase
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2009.12.008

Anterior Gradient 2 (AGR2) is a protein disulfide isomerase that plays important roles in diverse processes in multiple cell lineages as a developmental regulator, survival factor and susceptibility gene for inflammatory bowel disease. Here, we show using germline and inducible
Agr2−/− mice that
Agr2 plays important roles in intestinal homeostasis.
Agr2−/− intestine has decreased goblet cell Mucin 2, dramatic expansion of the Paneth cell compartment, abnormal Paneth cell localization, elevated endoplasmic reticulum (ER) stress, severe terminal ileitis and colitis. Cell culture experiments show that
Agr2 expression is induced by ER stress, and that siRNA knockdown of
Agr2 increases ER stress response. These studies implicate
Agr2 in intestinal homeostasis and ER stress and suggest a role in the etiology of inflammatory bowel disease.