Targeted inactivation of the mouse guanylin gene results in altered dynamics of colonic epithelial proliferation.
Heat-stable enterotoxin (STa), elaborated by enterotoxigenic Echerichia coli, is a worldwide cause of secretory diarrhea in infants and travelers. Both STa and guanylin, a peptide structurally similar to STa, increase intracellular cGMP levels after binding to the same intestinal receptor, guanylate cyclase C (GC-C). Distinct from its role as an intestinal secretagogue, guanylin may also have a role in intestinal proliferation, as guanylin expression is lost in intestinal adenomas. To determine the function of guanylin in intestinal epithelia, guanylin null mice were generated using a Cre/loxP-based targeting vector. Guanylin null mice grew normally, were fertile and showed no signs of malabsorption. However, the levels of cGMP in colonic mucosa of guanylin null mice were significantly reduced. The colonic epithelial cell migration rate was increased and increased numbers of colonocytes expressing proliferating cell nuclear antigen (PCNA) were present in crypts of guanylin null mice as well. The apoptotic index was similar in guanylin null mice and littermate controls. We conclude from these studies that loss of guanylin results in increased proliferation of colonic epithelia. We speculate that the increase in colonocyte number is related to decreased levels of cGMP and that this increase in proliferation plays a role in susceptibility to intestinal adenoma formation and/or progression.
Steinbrecher
Kris A
KA
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital Research Foundation, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Wowk
Steve A
SA
Rudolph
Jeffrey A
JA
Witte
David P
DP
Cohen
Mitchell B
MB
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D003106:Colon / Q000033:anatomy & histology / Q000473:pathology*; D006152:Cyclic GMP / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D005768:Gastrointestinal Hormones; D020868:Gene Silencing; D018390:Gene Targeting; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D045265:Natriuretic Peptides; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011995:Recombination, Genetic
D005768:Gastrointestinal Hormones; D045265:Natriuretic Peptides; D010455:Peptides; D018809:Proliferating Cell Nuclear Antigen; C072685:guanylin; D006152:Cyclic GMP