The intestinal epithelium has a remarkable capacity for self-renewal. This renewal is fuelled by intestinal stem cells that give rise to a variety of intestinal epithelial cell types, including secretory cells such as Paneth and goblet cells. Here, Ruth Schmidt-Ullrich and colleagues report that the transcription factor NF-κB, which has been implicated in intestinal tumorigenesis and inflammation, controls Paneth versus goblet cell fate decisions in the mouse small intestine. Using reporter lines, the researchers first show that NF-κB activity is high in Paneth cells and secretory progenitors. They further demonstrate that intestinal epithelial cell proliferation and death are unaltered in mice with ubiquitous suppression of NF-κB activity (ΔN mice) but that goblet cell numbers increase at the expense of Paneth cells; the few Paneth cells that do form exhibit perturbed maturation. The authors also report that crypt organoids derived from ΔN mice show reduced growth, an increase in goblet cells and a loss of Paneth cells. Moreover, the expression of Wnt3, Wnt10A and the Wnt target Sox9 is disrupted in these mice/organoids. However, although Wnt3 addition rescues the growth phenotype of the organoids, it does not rescue Paneth-goblet cell numbers, suggesting that other Wnts may be at play. Overall, these findings uncover a new role for NF-κB in controlling cell fate decisions and differentiation in the intestine.
