Transforming growth factor α disrupts the normal program of cellular differentiation in the gastric mucosa of transgenic mice

Richard Sharp, Mark W. Babyatsky, Hitoshi Takagi, Sven Tågerud, Timothy C. Wang, Dale E. Bockman, Stephen J. Brand, Glenn Merlino

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Transforming growth factor alpha (TGFα) evokes diverse responses in transgenic mouse tissues in which it is overexpressed, including the gastric mucosa, which experiences aberrant growth and a coincident repression of hydrochloric acid production. Here we show that ectopically expressed TGFα induces an age-dependent cellular reorganization of the transgenic stomach, in which the surface mucous cell population in the gastric pit is greatly expanded at the expense of cells in the glandular base. Immunohistochemical analysis of BrdU incorporation into DNA demonstrated that although mature surface mucous cells were not proliferating, DNA synthesis was enhanced by approximately 67% in the glandular base and isthmus, where progenitor cells reside, RNA blot and in situ hybridization were employed to determine temporal and spatial expression patterns of specific markers representing a variety of exocrine and endocrine gastric cell types. Mature parietal and chief cells were specifically depleted from the glandular mucosa, as judged by a 6- to 7-fold decrease in the expression of genes encoding H+,K+-ATPase, which is required for acid secretion, and pepsinogen C. respectively. The reduction of these markers coincided in time with the activation of TGFα transgene expression in the neonatal stomach. The rate of cell death in the glandular region was not overtly different. Significantly, the loss of parietal and chief cells occurred without a concomitant loss of their respective cellular precursors, In contrast to exocrine cells, D and G endocrine cells were much less severely affected, based on analysis of somatostatin and gastrin expression. Analysis of these dynamic changes indicates that TGFα can induce selective alterations in terminal differentiation and proliferation in the gastric mucosa, and suggests that TGFα plays an important physiological role in the normal regulation of epithelial cell renewal.

Original languageEnglish (US)
Pages (from-to)149-161
Number of pages13
JournalDevelopment
Volume121
Issue number1
StatePublished - Jan 1 1995

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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    Sharp, R., Babyatsky, M. W., Takagi, H., Tågerud, S., Wang, T. C., Bockman, D. E., Brand, S. J., & Merlino, G. (1995). Transforming growth factor α disrupts the normal program of cellular differentiation in the gastric mucosa of transgenic mice. Development, 121(1), 149-161.