Guanylyl Cyclase C Regulates the Intestinal Crypt‐Villus Axis

Abstract

Guanylyl cyclase C (GCC), the receptor for diarrheagenic bacterial heat-stable enterotoxins (STs) and the endogenous ligands guanylin and uroguanylin, is specifically expressed in apical membranes of intestinal epithelial cells where it regulates fluid and electrolyte secretion. However, a novel paradigm is emerging in which GCC signaling regulates the proliferation of human colon carcinoma cells. Here, the role of GCC in regulating enterocyte dynamics along the crypt-villus axis was examined. GCC target-inactivated (GCC−/−) mice exhibit elongated crypts from the duodenum to the colon, populated by more rapidly cycling progenitor cells. Further, enterocytes exhibited increased rates of migration and apoptosis, but decreased differentiation, along the crypt-villus axis of GCC−/− mice. Moreover, activation of GCC reduced proliferation of cells in human normal colonic mucosa obtained from patients and inhibited cell cycle progression of NCM460 human colonic crypt cells. Indeed, GCC delayed G1/S cell cycle transition which was mediated by cGMP-dependent protein kinase. These data demonstrate that GCC contributes to the homeostatic transition from proliferation to differentiation along the intestinal crypt-villus axis. Since expression of the endogenous ligands is frequently lost during colorectal carcinogenesis, GCC may represent a novel intestinal tumor suppressor.