A Phyllopod-Mediated Feedback Loop Promotes Intestinal Stem Cell Enteroendocrine Commitment in Drosophila

The intestinal epithelium in the Drosophila midgut is maintained by intestinal stem cells (ISCs), which are capable of generating both enterocytes and enteroendocrine cells (EEs) via alternative cell fate specification. Activation of Delta-Notch signaling directs ISCs for enterocyte generation, but how EEs are generated from ISCs remains poorly understood. Here, we identified Phyllopod (Phyl) as a key regulator that drives EE generation from ISCs. Phyl, which is normally suppressed by Notch, functions as an adaptor protein that bridges Tramtrack 69 (Ttk69) and E3 ubiquitin ligase Sina for degradation. Degradation of Ttk69 allows the activation of the Achaete-Scute Complex (AS-C)-Pros regulatory axis, which promotes EE specification. Interestingly, expression of AS-C genes in turn further induces Phyl expression, thereby establishing a positive feedback loop for continuous EE fate specification and commitment. This positive feedback circuit-driven regulatory mechanism could represent a common strategy for reliable and irreversible cell fate determination from progenitor cells.