Sox4 Promotes Atoh1-Independent Intestinal Secretory Differentiation Toward Tuft and Enteroendocrine Fates

Abstract

We found Sox4 promoted tuft and enteroendocrine cell lineage allocation independently of Atoh1. These results challenge the longstanding model in which Atoh1 is the sole regulator of secretory differentiation in the intestine and are relevant for understanding epithelial responses to parasitic infection.

Commensal-derived succinate enhances tuft cell specification and suppresses ileal inflammation

“…Tuft cell placement was non-secretory in 83% of wildtype trajectories and secretory in the remaining 17% ( Figure 2H). These results supported recent findings regarding an alternative origin of small intestinal tuft cells that is separate from the Atoh1-dependent secretory lineages Gracz et al, 2018). p-Creode analysis of the TNF ΔARE/+ scRNA-seq dataset illustrated that, even under inflammatory conditions, tuft cells shared a trajectory with the absorptive lineage ( Figures 2F, S5B).…”

“…Quantification of immunofluorescence staining confirmed that AtohKO animals lacked MUC2+ goblet cells and LYZ1+ Paneth cells (Figures 1D, 1G-1H), consistent with their classification in the Atoh1dependent secretory lineage (Vandussen & Samuelson, 2010;Shroyer et al, 2007;Noah et al, 2011). However, in contrast to the established hierarchy, we observed a significant increase in DCLK1+ tuft cells throughout the small intestine ( Figure 1E), which supports more recent studies suggesting tuft cells can be specified outside the Atoh1-dependent secretory lineage Gracz et al, 2018). In addition, we observed an increased presence of MPO+ neutrophils in the villi of AtohKO animals, reflecting a baseline level of inflammation, similar to the less inflamed regions of TNF ΔARE/+ animals, potentially due to goblet and Paneth cell loss ( Figure 1F).…”

“…We performed scRNA-seq in wildtype, TNF ΔARE/+ , and AtohKO animals to examine gene expression changes in small intestinal tuft cells. Analysis of wildtype and TNF ΔARE/+ scRNA-seq datasets using the p-Creode algorithm confirmed a non-secretory origin for epithelial tuft cells, independent of the Atoh1-dependent secretory lineage(Gracz et al, 2018). In the AtohKO model, we applied both trend dynamic and population analysis to demonstrate that expression of TCA cycle genes was upregulated.…”

“…In acute mouse models of infection, helminths colonize the proximal small intestine and (Gerbe et al, 2009(Gerbe et al, , 2011. Recent studies have demonstrated that small intestinal tuft cells may have an alternative lineage specification route Gracz et al, 2018) that may depend on cues from luminal microorganisms (Wilen et al, 2018). Despite the inverse relationship between incidence of parasitic infections and rates of IBD diagnoses, there is very little known about the functional role of tuft cells in human disease.…”

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33

“…Spry2 IEKO mice showed an increase in the number of both tuft and goblet cells, but not enteroendocrine cells. The differential regulation of secretory cells suggests an additional modulator of secretory pathways may be required for enteroendocrine specification 27 . As secretory cells have been linked to barrier integrity maintenance 28 , we also tested whether Spry2 deletion modulated epithelial barrier function.…”