The maturation of mucus-secreting gastric epithelial progenitors into digestive-enzyme secreting zymogenic cells requires Mist1
- 1 January 2007
- journal article
- Published by The Company of Biologists in Development
- Vol. 134 (1), 211-222
- https://doi.org/10.1242/dev.02700
Abstract
Continuous regeneration of digestive enzyme (zymogen)-secreting chief cells is a normal aspect of stomach function that is disrupted in precancerous lesions (e.g. metaplasias, chronic atrophy). The cellular and genetic pathways that underlie zymogenic cell (ZC) differentiation are poorly understood. Here, we describe a gene expression analysis of laser capture microdissection purified gastric cell populations that identified the bHLH transcription factor Mist1 as a potential ZC regulatory factor. Our molecular and ultrastructural analysis of proliferation, migration and differentiation of the gastric unit in Mist1-/- and control mice supports a model whereby wild-type ZC progenitors arise as neck cells in the proliferative (isthmal) zone of the gastric unit and become transitional cells (TCs) with molecular and ultrastructural characteristics of both enzyme-secreting ZCs and mucus-secreting neck cells as they migrate to the neck-base zone interface. Thereafter, they rapidly differentiate into mature ZCs as they enter the base. By contrast, Mist1-/- neck cells differentiate normally, but ZCs in the mature, basal portion of the gastric unit uniformly exhibit multiple apical cytoplasmic structural abnormalities. This defect in terminal ZC differentiation is also associated with markedly increased abundance of TCs, especially in late-stage TCs that predominantly have features of immature ZCs. Thus, we present an in vivo system for analysis of ZC differentiation, present molecular evidence that ZCs differentiate from neck cell progenitors and identify Mist1 as the first gene with a role in this clinically important process.This publication has 31 references indexed in Scilit:
- The Hedgehog Signalling Pathway in the Gastrointestinal Tract: Implications for Development, Homeostasis, and DiseaseGastroenterology, 2005
- Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient miceAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2005
- Building an antibody factory: a job for the unfolded protein responseNature Immunology, 2004
- Gastric Cancer Originating from Bone Marrow-Derived CellsScience, 2004
- Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zoneGut, 2004
- Inhibition of Mist1 Homodimer Formation Induces Pancreatic Acinar-to-Ductal MetaplasiaMolecular and Cellular Biology, 2004
- Molecular Characterization of Mouse Gastric Zymogenic CellsOnline Journal of Public Health Informatics, 2003
- Exocrine specific expression of Connexin32 is dependent on the basic helix-loop-helix transcription factor Mist1Journal of Cell Science, 2003
- Defining Epithelial Cell Progenitors in the Human Oxyntic MucosaThe International Journal of Cell Cloning, 2003
- Dynamics of epithelial cells in the corpus of the mouse stomach. I. Identification of proliferative cell types and pinpointing of the stem cellThe Anatomical Record, 1993