Abstract
The extreme chemical and mechanical forces endured by the gastrointestinal tract drive a constant renewal of the epithelial lining. Stem cells of the intestine and stomach, marked by the cell surface receptor Lgr5, preserve the cellular status-quo of their respective tissues through receipt and integration of multiple cues from the surrounding niche. Wnt signalling is a critical niche component for gastrointestinal stem cells and we have previously shown that the Wnt receptor, Frizzled-7 (Fzd7), is required for gastric homeostasis and the function of Lgr5+ intestinal stem cells. Additionally, we have previously shown a requirement for the Wnt target gene Myc in intestinal homeostasis, regeneration and tumourigenesis. However, it is unknown whether Fzd7 or Myc have conserved functions in gastric Lgr5+ stem cells. Here we show that gastric Lgr5+ stem cells do not require Fzd7 or Myc and are able to maintain epithelial homeostasis, highlighting key differences in the way Wnt regulates homeostasis and Lgr5+ stem cells in the stomach compared to the intestinal epithelium. Furthermore, deletion of Myc throughout the epithelium of the gastric antrum has no deleterious effects suggesting therapeutic targeting of Myc in gastric cancer patients will be well tolerated by the surrounding normal tissue.
Highlights
The epithelium of the gastrointestinal tract encounters substantial chemical and physical stresses.One of the mechanisms that has evolved to help cope with these harsh conditions is the continuous turnover of the epithelium, in which new cells are generated from populations of stem cells
Lineage tracing proceeded in the Fzd7 deficient Lgr5CreERT2 ; Fzd7fl/fl ; LacZLSL mice indicating that Fzd7 loss is not deleterious to Lgr5+ cells in the gastric antrum, and these stem cells can function without Fzd7
RT-qPCR for Fzd genes in cells FACS sorted for high GFP expression from the antrum epithelium of Lgr5CreEGFP-ERT2 mice revealed that Fzd7 expression was undetectable (Figure 1E), supporting our in vivo observations that Lgr5+ cells in the gastric antrum are regulated differently from those in the intestinal epithelium, and do not require Fzd7
Summary
The epithelium of the gastrointestinal tract encounters substantial chemical and physical stresses.One of the mechanisms that has evolved to help cope with these harsh conditions is the continuous turnover of the epithelium, in which new cells are generated from populations of stem cells. Lgr was first identified as a Wnt target gene and a marker of highly proliferative stem cells located at the base of the intestinal crypts that fuel the constant turnover of cells [1]. It has since been confirmed as a stem cell marker in several epithelial tissues including the stomach [2,3], hair follicle [4], ovary [5], mammary gland [6] and kidney [7].
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