mTORC1-dependent control of Hedgehog signaling mediates nutrient-responsive licensing of intestinal stem cell differentiation

How progenitor cells couple their metabolic state to the regulation of fate and differentiation remains a fundamental question in tissue development and regeneration. Here, we identify a nutrient-responsive circuit that links progenitor anabolism to differentiation in the Drosophila midgut. We show that the mTORC1 downstream effector PWP1 is necessary and sufficient for differentiation of intestinal stem cell progeny toward the absorptive lineage in fed animals. In progenitors with high mTORC1 activity, PWP1 controls gene expression to promote Hedgehog (Hh) signaling, which cell autonomously drives progenitor differentiation into enterocytes. This circuit is constrained by feedback regulation, as elevated Hh activity inhibits mTORC1 and consequently excludes PWP1 from the nucleus. Disruption of the mTORC1-PWP1-Hh axis causes a progressive failure of enterocyte turnover during aging and reduced lifespan. While the aged midguts retain their barrier function, defective renewal leads to aging-associated deregulation of intestinal metabolism. Collectively, these observations support the concept of growth-dependent licensing of differentiation, whereby the nutrient-responsive anabolic state of a progenitor cell controls its lineage progression, consequently enabling organ renewal.