STIMULATION OF ACTIVIN RECEPTOR-II SIGNALING PATHWAYS INHIBITS DIFFERENTIATION OF MULTIPLE GASTRIC EPITHELIAL LINEAGES

Activins are TGF beta family members known to mediate a variety of dev elopmental events, We examined the effects of activins on the self-ren ewing epithelial lineages present in gastric units of the adult mouse stomach, These lineages are descended from multipotent stem cells loca ted in the midportion of each unit. The stem cell and its immediate de scendants can be identified by their morphological features, Studies o f knockout mice lacking activins A or B, and/or activin type II recept ors (ActRII) revealed that ActRII-mediated signaling is not required f or normal gastric epithelial morphogenesis or homeostasis. Mice homozy gous for a null allele of the alpha-inhibin gene (inha(m1/m1)) develop gonadal sex cord stromal tumors that secrete large amounts of activin s A and B. Analysis of inha(m1/m1) mice, with or without gonads, estab lished that supraphysiological levels of activins block differentiatio n of preparietal to acid-producing parietal cells, differentiation of neck cells to pepsinogen-producing zymogenic cells, and terminal diffe rentiation of mucus-producing pit cells, ActRII mRNA is normally prese nt in pit, parietal, and zymogenic cells, inha(m1/m1)actRII(m1/m1) com pound homozygotes develop activin-secreting gonadal tumors but have no abnormalities in their gastric epithelium, indicating that persistent stimulation of ActRII-dependent signaling pathways produces pleiotrop hic effects on gastric epithelial differentiation. When a lineage-spec ific promoter is used to ablate mature parietal cells with an attenuat ed diphtheria toxin A fragment in transgenic mice, there is increased proliferation of the multipotent gastric stem cell and its committed d aughters and subsequent development of gastric neoplasia. Parietal cel l loss in inha(m1/m1) mice is not associated with this proliferative r esponse, These different responses to parietal cell loss suggest that stimulation of ActRII-dependent signaling pathways in inha(m1/m1) anim als affects the proliferative activity of the stem cell and its immedi ate descendents. This finding may have therapeutic significance.