Requirement of the Epithelium-specific Ets Transcription Factor Spdef for Mucous Gland Cell Function in the Gastric Antrum
Requirement of the Epithelium-specific Ets Transcription Factor Spdef for Mucous Gland Cell Function in the Gastric Antrum
复制标题
DOI：
10.1074/jbc.m110.164541
复制
发表时间：
2010-11-05
影响因子：
4.8
通讯作者：
Libermann, Towia A.
中科院分区：
文献类型：
--
作者：
Horst, David;Gu, Xuesong;Libermann, Towia A.
胃上皮的粘液分泌细胞提供了一种保护屏障，以抵御细菌定植或其他刺激可能导致的损害。屏障功能受损会导致慢性炎症和癌症。上皮特异性转录因子SPDEF(又称Pdef)基因敲除的小鼠在肠道和支气管分泌细胞的终末分化方面存在缺陷。我们试图确定SPDEF在胃中的生理功能，这是SPDEF表达水平显著的另一个部位。我们使用原位杂交和免疫组织化学方法定位小鼠胃中表达SPDEF的细胞；定向基因干扰产生缺乏SPDEF的小鼠；以及组织学、免疫学和转录图谱方法来确定SPDEF在胃上皮细胞动态平衡中的需求。在野生型小鼠中，SPDEF的RNA和蛋白主要在胃窦的粘液腺细胞和腺体的粘液颈细胞中表达。在一年半的时间里，近一半的纯合子突变小鼠出现了严重的胃窦粘膜增生。粘膜下炎性细胞的渗出先于胃窦增生数周。SPDEF的缺失损害了胃窦粘液腺细胞的终末成熟，表现为Muc6和Tff2的表达减少，分泌颗粒减少。胃窦基因表达异常与SPDEF(-/-)结肠显著重叠，包括与分泌颗粒运输和功能有关的基因。胃窦粘液腺细胞的终末成熟需要SPDEF，以保护动物免受胃炎症和由此导致的增生。这些要求与SPDEF在分泌肠道细胞中的功能平行，并提示了胃肠道分泌谱系成熟的共同分子机制。
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.