Early activation of Wnt β-catenin system following a massive small bowel resection in mice

Abstract

Introduction. Recent evidence supports a role for the Wnt β-catenin system in the regulation of intestinal proliferation, migration, and differentiation towards secretory lineages in mature epithelium. The observation that early increased allocation of secretory lineages (Paneth, goblet, and enteroendocrine cells) within intestinal epithelium occurs following a massive small bowel resection (SBR) suggest activation of the Wnt β-catenin system may initiate the adaptive response following resection. The purpose of this study was to determine early changes in gene expression of the soluble intestinal Wnts and their downstream targets responsible for proliferation ( c-myc), migration (EphrinB1 and B2), and Paneth cell differentiation (EphB3). Methods. Male mice (C57/BL6J, 22–25 g) were randomized to either a sham operation (transection and reanastomosis) or 50% SBR (mid-jejunum to proximal ileum). All animals ( n = 5–8 per group) were maintained on liquid diet 12 h following surgery. Terminal ileum was harvested at 6 h, 12 h, 36 h, 3 days, and 7 days following surgery and RNA was isolated. Quantitative real-time RT-PCR was utilized to determine the expression of Wnt4, Wnt6, c-myc, EphB3, EphrinB1, and EphrinB2 mRNAs. Fold change between SBR and sham was determined at each time point. Statistical analysis utilized one-way ANOVA ( P < 0.05). Results. SBR resulted in early increased expression of Wnt4 (1.6-fold) by 12 h, which returned to baseline by 3 days. Significantly increased expression of c-myc occurred at 36 h (1.9-fold), peaked at 3 days (3.2-fold), and returned to baseline by 7 days. EphB3 (14.3-fold), a marker of Paneth cells, and Ephrin B2 (4.9-fold), peaked at 3 days and returned to baseline by 7 days. Conclusion. Massive intestinal resection results in early increased expression of Wnts, followed by increases in their downstream targets regulating proliferation (c-myc) and differentiation (EphB3) and cell migration (Ephrin B2). Early activation of the Wnt β-catenin pathway may be responsible for initiating intestinal adaptation.