title: Glucagon-Like Peptide-2 Requires a Full Complement of Bmi-1 for Its Proliferative Effects in the Murine Small Intestine.
abstract: The intestinal hormone, glucagon-like peptide-2 (GLP-2), stimulates growth, survival, and function of the intestinal epithelium through increased crypt cell proliferation, and a long-acting analog has recently been approved to enhance intestinal capacity in patients with short bowel syndrome. The goal of the present study was to determine whether GLP-2-induced crypt cell proliferation requires a full complement of B-cell lymphoma Moloney murine leukemia virus insertion region-1 homolog (Bmi-1), using the Bmi-1(eGFP/+) mouse model in comparison with age- and sex-matched Bmi-1(+/+) littermates. Bmi-1 is a member of the polycomb-repressive complex family that promotes stem cell proliferation and self-renewal and is expressed by both stem cells and transit-amplifying (TA) cells in the crypt. The acute (6 h) and chronic (11 d) proliferative responses to long-acting human (Gly(2))GLP-2 in the crypt TA zone, but not in the active or reserve stem cell zones, were both impaired by Bmi-1 haploinsufficiency. Similarly, GLP-2-induced crypt regeneration after 10-Gy irradiation was reduced in the Bmi-1(eGFP/+) animals. Despite these findings, chronic GLP-2 treatment enhanced overall intestinal growth in the Bmi-1(eGFP/+) mice, as demonstrated by increases in small intestinal weight per body weight and in the length of the crypt-villus axis, in association with decreased apoptosis and an adaptive increase in crypt epithelial cell migration rate. The results of these studies therefore demonstrate that a full complement of Bmi-1 is required for the intestinal proliferative effects of GLP-2 in both the physiological and pathological setting, and mediates, at least in part, the proliferation kinetics of cells in the TA zone.
authors.affiliation: Departments of Physiology (B.R.S., H.Y.M.P., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Smither
authors.affiliation: Departments of Physiology (B.R.S., H.Y.M.P., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Hilary Y M
authors.initials: HY
authors.lastname: Pang
authors.affiliation: Departments of Physiology (B.R.S., H.Y.M.P., P.L.B.) and Medicine (P.L.B.), University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects* / Q000502:physiology; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C489421:Bmi1 protein, mouse; D053767:Glucagon-Like Peptide 2; D011518:Proto-Oncogene Proteins; D063150:Polycomb Repressive Complex 1