Abstract
Mucus-secreting cells of the stomach epithelium provide a protective barrier against damage that might result from bacterial colonization or other stimuli. Impaired barrier function contributes to chronic inflammation and cancer. Knock-out mice for the epithelium-specific transcription factor Spdef (also called Pdef) have defects in terminal differentiation of intestinal and bronchial secretory cells. We sought to determine the physiologic function of Spdef in the stomach, another site of significant levels of Spdef expression. We used in situ hybridization and immunohistochemistry to localize Spdef-expressing cells in the mouse stomach; targeted gene disruption to generate mice lacking Spdef; and histologic, immunologic, and transcriptional profiling approaches to determine the requirements of Spdef in stomach epithelial homeostasis. In wild-type mice, Spdef RNA and protein are expressed predominantly in mucous gland cells of the antrum and in mucous neck cells of the glandular corpus. Within 1.5 years, nearly half of homozygous mutant mice developed profound mucosal hyperplasia of the gastric antrum. Submucosal infiltration of inflammatory cells preceded antral hyperplasia by several weeks. The absence of Spdef impaired terminal maturation of antral mucous gland cells, as reflected in reduced expression of Muc6 and Tff2 and reduced numbers of secretory granules. Antral gene expression abnormalities overlapped significantly with those in Spdef(-/-) colon, including genes implicated in secretory granule traffic and functions. Spdef is required for terminal maturation of antral mucous gland cells to protect animals from gastric inflammation and resulting hyperplasia. These requirements parallel Spdef functions in secretory intestinal cells and suggest a common molecular mechanism for maturation of gastrointestinal secretory lineages.
Highlights
The Ets protein family in humans and mice contains nearly 30 transcription factors
Exposure to intratracheal allergens or IL-13 leads to excess mucus production as a result of Spdef-dependent goblet cell differentiation, whereas Spdef expression in transgenic bronchial epithelium causes goblet cell hyperplasia and mucus hypersecretion [17], defects related to human lung diseases
Gastric Antral Mucous Gland Cell Maturation erated an independent null allele for Spdef, and here we report on the requirement for this epithelial Ets factor in the mammalian stomach
Summary
Among the three major stomach compartments, Spdef expression is highest in the antrum, followed by the corpus, and absent in the forestomach (Fig. 1B) To corroborate these findings and to identify Spdefexpressing cell types, we performed immunohistochemistry with a well characterized Ab [17]. Arrays with Ͻ5% outlier ground staining of chief (zymogenic) cells in the corpus conprobes were used to identify differential expression Results founded these efforts (data not shown), we consistently were normalized using the Robust Multichip Average algo- observed a specific signal at the base of antral glands with antirithm in Bioconductor, based on background correction, nor- sense but not with sense probes (Fig. 1F); riboprobe specificity malization, and summarization of signal values [25, 27]. The expres- prominent expression in the antrum. sion data matrix was row-normalized for each gene prior to Generation of SpdefϪ/Ϫ Mice—We used homologous recomapplication of average linkage clustering
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