SUMMARY
γ-secretase inhibitors (GSIs) have been recently proposed as chemopreventive agents in gastrointestinal neoplasia, because they lead, through inhibition of the Notch signaling pathway, to goblet cell conversion in some intestinal adenomas of the ApcMin mice, and halt epithelial cell proliferation. In this study, we examine in depth, in normal mice, the effects of a GSI, dibenzazepine (DBZ), intraperitoneally administered for 8 days at a non toxic dose, on the gene expression pattern of secretory mucin (MUC), goblet cell conversion, organization of the crypt structural-proliferative units, stem cell niche and apoptotic compartments, along the entire length of the small intestine and colon. We demonstrate that DBZ elicits a homogeneous goblet cell conversion all along the mouse intestinal tract, associated with an overexpression of the gene Muc2 without ectopic expression of the gastric genes Muc5ac and Muc6, and with the emergence of lysozyme-positive ‘intermediate cells’ in the colon. Furthermore, DBZ treatment induces a heterogeneous reorganization of the crypt structural-proliferative units along the intestinal tract and of the stem cell niche in the colon, without disturbing the apoptotic compartment. These findings point to uncoupled effects of a GSI on goblet cell conversion and reorganization of the intestinal crypt structural-proliferative units and stem cell niche, and suggest caution in the use of GSIs as chemopreventive agents for intestinal neoplasia.
- Received January 6, 2011.
- Accepted July 28, 2011.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms
Article navigation
Related articles
Cited by...
More in this TOC section
Similar articles
Other journals from The Company of Biologists
Featured resource: A classification system for zebrafish adipose tissues
A new Resource article from James Minchin and John Rawls presents a standardized nomenclature and classification system for zebrafish adipose tissues, and regression models to predict expected adipose size during the course of zebrafish development.
Why should you publish your next paper in Disease Models & Mechanisms?
From single-celled organisms to patient-derived models, cancer to neurodegeneration, Disease Models & Mechanisms publishes the best original research and resources that focus on the use of model systems to better understand, diagnose and treat human disease. Submit your paper here.
Editor's choice: a powerful new model for neuropsychiatric disorders
A new Drosophila model to study the role of schizophrenia-associated gene PRODH in behavioural disorders has been developed by a team lead by Patrick Callaerts from the University of Leuven in Belgium. Their Research article describes how this model reveals that precise regulation of proline metabolism in the lateral neurons ventral region of the brain is crucial for maintaining normal behaviour patterns. Read a press release on the discovery here.
Focus on lysosomal storage diseases
In the latest issue, we present two new articles focused on lysosomal storage diseases (LSDs). A Research article from Michael Hoch and co-authors presents a detailed analysis of lipid accumulation, lysosomal dysfunction and neurodegeneration in a Drosophila sphingolipidosis model, while Ellen Sidransky et al. discuss how iPSCs provide new opportunities to explore the biology and pathophysiology of LSDs in a new Review.
Transfer to Biology Open
If your submission to Disease Models & Mechanisms is unsuccessful, did you know you can transfer your paper and any reviews directly to our sister journal, Biology Open? The majority of papers transferred with reviews are accepted for publication. Find out how here.