Basic—Alimentary TractDll1- and Dll4-Mediated Notch Signaling Are Required for Homeostasis of Intestinal Stem Cells
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Animals
All animal work was conducted according to Swiss national guidelines. This study has been reviewed and approved by the Service Vétérinaire Cantonal of Etat de Vaud. All NIP1::CreERT2 study-related animals were housed in the Washington University mouse facility and were approved by the Animal Studies Committee of Washington University.
The Cre-ERT2 recombinase activity was induced by injecting 2- to 3-week-old mice with tamoxifen (10 mg/kg body weight in corn oil; Sigma-Aldrich, Buchs,
Notch1 Activation Occurs in Adult Intestinal Stem Cells
Notch signaling in the intestine plays an important role as a gatekeeper of progenitor cells and also as a regulator of the absorptive/secretory lineage.5, 6 To gain further insight whether Notch signaling might also occur at the level of adult intestinal SCs, we generated a tamoxifen-inducible Notch1 activation-dependent reporter knock-in mouse line, NIP1::CreERT2 (Figure 1A).17 The intracellular domain of the targeted Notch1 allele was replaced with a complementary DNA encoding a 6×
Discussion
It is now well established that both Wnt and Notch signaling are essential for the maintenance of the proliferative crypt compartment. Both pathways are also involved in cellular differentiation processes of the intestinal epithelium.3 Loss of Notch signaling due to genetic inactivation of the RBP-J gene, or as a consequence of using pharmacologic γ-secretase inhibitors or blocking antibodies, results in the loss of proliferating crypt progenitors, which convert into postmitotic goblet cells.5,
Acknowledgments
The authors thank C. S. Nowell for discussion and critical reading of the manuscript and the animal and histology facilities at Ecole Polytechnique Fédérale de Lausanne for their assistance.
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by the Swiss National Science Foundation, the Swiss Cancer League, EuroSyStem, OptiStem (F.R.) and EMBO (V.R.), the National Institute of Diabetes and Digestive and Kidney Diseases (K.H.K.), Cancer Research UK (J.L.), and National Institutes of Health grant DK066408 (to Z.L., S.C., and R.K.).