Growth retardation, duodenal lesions, and aberrant ileum architecture in triple null mice lacking EGF, amphiregulin, and TGF-alpha

Background & Aims: Mice lacking epidermal growth factor (EGF), transforming growth factor alpha, and amphiregulin were used to identify roles for thes e EGF receptor (EGFR) ligands in gastrointestinal development and mucosal i ntegrity. Methods: Gastrointestinal tract development was examined in knock out mice and correlated with expression of EGF-R protein and EGF family mem bers throughout the gut. Crossfostering experiments addressed roles of mate rnal- and neonatal-derived ligands in pup growth and intestinal development . Cysteamine-induced ulceration in EGF(-/-) mice was used to examine its ro le in mucosal cytoprotection. Results: Neonatal mice lacking all 3 ligands were growth retarded, even when reared by wild-type dams; conversely, lack of maternal ligands transiently impaired wild-type pup growth. Triple null neonates displayed spontaneous duodenal lesions, and ileal villi were trunc ated and fragile with reduced cellular proliferation in the crypts. However , maturation of digestive enzymes was unaffected. Adult EGF(-/-) mice displ ayed more severe lesions in response to cysteamine treatment compared with wild-type counterparts, although triple null mice were not more susceptible to dextran sulfate sodium-induced colitis, suggesting a differential role for these ligands in the injury response. Conclusions: EGF-R ligands are re quired for development and mucosal maintenance in mouse small intestine. Bo th maternal and neonatal sources of growth factors are required for optimal pup growth.