Wnt/β-catenin signaling within multiple cell types dependent upon regulates intestinal stem cell proliferation.

The gut epithelium is subject to constant renewal, a process reliant upon intestinal stem cell (ISC) proliferation that is driven by Wnt/β-catenin signaling. Despite the importance of Wnt signaling within ISCs, the relevance of Wnt signaling within other gut cell types and the underlying mechanisms that modulate Wnt signaling in these contexts remain incompletely understood. Using challenge of the midgut with a non-lethal enteric pathogen, we examine the cellular determinants of ISC proliferation, harnessing , a recently identified regulator of Wnt signaling pathways, as a mechanistic tool. We find that Wnt signaling within Prospero-positive cells supports ISC proliferation and that regulates Wnt signaling in this context by antagonizing , a Cullin-3 E3 ligase adaptor that mediates Dishevelled polyubiquitination. This work establishes as a physiological regulator of Wnt/β-catenin signaling and suggests enteroendocrine cells as a new cell type that regulates ISC proliferation via Wnt/β-catenin signaling.