β-Catenin and TCF Mediate Cell Positioning in the Intestinal Epithelium by Controlling the Expression of EphB/EphrinB

Abstract

In the small intestine, the progeny of stem cells migrate in precise patterns. Absorptive, enteroendocrine, and goblet cells migrate toward the villus while Paneth cells occupy the bottom of the crypts. We show here that beta-catenin and TCF inversely control the expression of the EphB2/EphB3 receptors and their ligand ephrin-B1 in colorectal cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3 genes reveals that their gene products restrict cell intermingling and allocate cell populations within the intestinal epithelium. In EphB2/EphB3 null mice, the proliferative and differentiated populations intermingle. In adult EphB3(-/-) mice, Paneth cells do not follow their downward migratory path, but scatter along crypt and villus. We conclude that in the intestinal epithelium beta-catenin and TCF couple proliferation and differentiation to the sorting of cell populations through the EphB/ephrin-B system.

Reduced blood pressure after smooth muscle EFNB2 deletion and the potential association of EFNB2 mutation with human hypertension risk

“…2 Although EPH members and EFN members share homology with their respective members, each member has its distinct function in different cellular processes. [3][4][5][6][7] In general, the EPH kinases interact with their EFN ligands on neighboring cells, because EPHs and EFNs are all cell surface molecules. 2 These molecules could be cleaved from the cell surface by enzymes such as ADAM10, 8,9 an unspecified matrix metalloproteinase, 10 or γ-secretase; 11 therefore, it is possible that the shed soluble fragments of EPH and EFN might be able to influence cells and tissues at a distance by blocking the interaction of EPHs and EFNs there.…”

“…3,4,[12][13][14][15][16][17][18][19][20][21][22] They are also vital in many biological processes; 5,6,23,24 however, until our recent publications, there were no studies investigating the roles of these molecules in blood pressure (BP) regulation.…”

Beyond tumorigenesis: cancer stem cells in metastasis

“…These signals exist as a delicate "Yin & Yang" balance between positive and negative regulators. Using genetic models, key factors of the Wnt signaling pathway have been shown to be essential for promoting stem cell self-renewal in various systems [14][15][16][17][18][19][20]. Notch and hedgehog signaling pathways have also been demonstrated to play crucial regulatory roles for self-renewal regulation of HSCs [21][22][23][24].…”

Wnt Signaling Inhibition Deprives Small Intestinal Stem Cells of Clonogenic Capacity

“…In agreement with the fluorescent microscopy images, we observed temporal downregulation in mRNA levels of genes specifically expressed in cells located at the bottom of the crypt. The genes included Paneth cell markers ephrin receptor B3 ( EphB3 ) and lysozyme 1 ( Lyz1 ) (van Es et al ., 2005) or genes with broader expression in various crypt cells such as division cycle associated 7 ( Cdca7 ), ephrin receptor B2 ( EphB2 ), naked cuticle homolog 1 ( Nkd1 ), and SRY (sex determining region Y)‐box 9 ( Sox9 ) (Batlle et al ., 2002; Schuijers et al ., 2015; Stancikova et al ., 2015). Remarkably, the most robust downregulation was recorded for three genes that encode Wnt signaling‐activated markers of ISCs achaete‐scute complex homolog 2 ( Ascl2 ), Lgr5 , and Troy (Fafilek et al ., 2013; van der Flier et al ., 2009).…”