Sox4 drives intestinal secretory differentiation toward tuft and enteroendocrine fates

Intestinal stem cells (ISCs) undergo differentiation following reduction of Notch signaling and activation of Atoh1, a master regulator of secretory fate. However, recent evidence suggests that rare tuft cells may differentiate via alternative mechanisms. Here, we examine the role of Sox4 in ISC fate decisions. Loss of Sox4 results in disruption of ISC function and secretory differentiation, including decreased numbers of enteroendocrine and tuft cells. Sox4 is activated following reduction of Notch signaling and required for response to signals that induce tuft cell hyperplasia, including IL-13 and parasitic helminth infection. Subsets of Sox4+ progenitors are transcriptomically similar to both actively dividing and mature tuft cells, and dissimilar from other secretory progenitors expressing Atoh1. Our data suggest that Sox4 drives an alternative, Notch-repressed secretory differentiation pathway independently of Atoh1, and challenge the status of Atoh1 as the sole initiator of secretory fate in the intestine.