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Department of Molecular Biology and Pharmacology (Q.L., J.I.G.)
Washington University School of Medicine St. Louis, Missouri
63110
Department of Anatomy (S.M.K.) Faculty of
Medicine Kuwait University Safat 13110, Kuwait
Departments of Pathology, Molecular and Human Genetics, and Cell
Biology (K.A.C., M.M.M.) Baylor College of Medicine Houston,
Texas 77030
Activins are TGFß family members known to
mediate a variety of developmental events. We examined the effects of
activins on the self-renewing epithelial lineages present in gastric
units of the adult mouse stomach. These lineages are descended from
multipotent stem cells located in the midportion of each unit. The stem
cell and its immediate descendants can be identified by their
morphological features. Studies of knockout mice lacking activins A or
B, and/or activin type II receptors (ActRII) revealed that
ActRII-mediated signaling is not required for normal gastric epithelial
morphogenesis or homeostasis. Mice homozygous for a null allele of the
-inhibin gene (inham1/m1) develop
gonadal sex cord stromal tumors that secrete large amounts of activins
A and B. Analysis of inham1/m1 mice, with
or without gonads, established that supraphysiological levels of
activins block differentiation of preparietal to acid-producing
parietal cells, differentiation of neck cells to pepsinogen-producing
zymogenic cells, and terminal differentiation of mucus-producing pit
cells. ActRII mRNA is normally present in pit, parietal, and zymogenic
cells.
inham1/m1actRIIm1/m1
compound homozygotes develop activin-secreting gonadal tumors but have
no abnormalities in their gastric epithelium, indicating that
persistent stimulation of ActRII-dependent signaling pathways produces
pleiotrophic effects on gastric epithelial differentiation. When a
lineage-specific promoter is used to ablate mature parietal cells
with an attenuated diphtheria toxin A fragment in transgenic mice,
there is increased proliferation of the multipotent gastric stem cell
and its committed daughters and subsequent development of gastric
neoplasia. Parietal cell loss in
inham1/m1mice is not associated with this
proliferative response. These different responses to parietal cell loss
suggest that stimulation of ActRII-dependent signaling pathways in
inham1/m1 animals affects the
proliferative activity of the stem cell and its immediate descendents.
This finding may have therapeutic significance.
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