A regional regulatory axis shapes enteroendocrine cell morphology and function

Enteroendocrine cells (EEs) are secretory cells in the gut epithelium that exist in two morphologically distinct forms: “open” and “closed.” However, the mechanisms governing this morphological divergence remain unclear. Here, we show that in the adult Drosophila midgut, open-type EEs are the predominant form throughout most regions, whereas the closed type is found exclusively in the middle gastric region (R3). We identify Ptx1, a region-specific transcription factor, as a key determinant of the closed EE morphology. Ptx1 maintains the expression of the Snail-family transcription factor escargot (esg) in newly formed EEs, which in turn suppresses the expression of smooth septate junction (sSJ) genes. This repression prevents apical integration into the epithelium, resulting in the formation of closed-type EEs. Ectopic expression of ptx1 or esg in non-R3 regions induces the formation of closed-type EEs, which exhibit impaired sensing of dietary amino acids. Together, our findings reveal a regional transcriptional regulatory axis that controls EE morphology and its associated luminal sensing function.