IGF-2 Is Necessary for Retinoblastoma-Mediated Enhanced Adaptation after Small-Bowel Resection

• DOI: 10.1007/s11605-014-2586-1
• Publication Date: 2014-07-07T18:16:39Z
• Authors: Pamela M. Choi; Raphael C. Sun; Josh Sommovilla; Jose Diaz-Miron; Jun Guo; Christopher R. Erwin; Brad W. Warner
• Keywords: Short Bowel Syndrome; Conditional gene knockout; Retinoblastoma; Intestinal epithelium; Knockout mouse

Previously, we have demonstrated that genetically disrupting retinoblastoma protein (Rb) expression in enterocytes results in taller villi, mimicking resection-induced adaption responses. Rb deficiency also results in elevated insulin-like growth factor-2 (IGF-2) expression in villus enterocytes. We propose that postoperative disruption of Rb results in enhanced adaptation which is driven by IGF-2. Inducible, intestine-specific Rb-null mice (iRbIKO) and wild-type (WT) littermates underwent a 50% proximal small-bowel resection (SBR) at 7-9 weeks of age. They were then given tamoxifen on postoperative days (PODs) 4-6 and harvested on POD 28. The experiment was then repeated on double knockouts of both IGF-2 and Rb (IGF-2 null/iRbIKO). iRbIKO mice demonstrated enhanced resection-induced adaptive villus growth after SBR and increased IGF-2 messenger RNA (mRNA) in ileal villus enterocytes compared to their WT littermates. In the IGF-2 null/iRbIKO double-knockout mice, there was no additional villus growth beyond what was expected of normal resection-induced adaptation. Adult mice in which Rb is inducibly deleted from the intestinal epithelium following SBR have augmented adaptive growth. IGF-2 expression is necessary for enhanced adaptation associated with acute intestinal Rb deficiency.