Spatiotemporal WNT and BMP gradients orchestrate regional enteroendocrine cell diversity along the Drosophila midgut

Enteroendocrine cells (EEs) in metazoan are diversified into multiple subtypes that occupy specific regions along the digestive tract to fulfill their functions. How to establish this regional pattern of EE subtypes is unclear. Here, we investigated the complex distribution patterns of three major EE subtypes along the length of the pupal and adult Drosophila midgut, and found that regional EE patterning is regulated by WNT and BMP signaling in a spatiotemporally dependent manner. Furthermore, there are both Notch-dependent and -independent cell division modes of EE progenitors that contribute to the generation of regional EE diversity. Our findings suggest that intercalated WNT and BMP morphogen gradients emanating from compartment boundaries play a critical role, not only in establishing regional ISC identity and the resulting EE diversity during development, but also in maintaining regional EE diversity in adulthood—a paradigm that may be conserved in mammals.