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

In the Drosophila midgut, mTORC1-dependent nuclear PWP1 is necessary and sufficient to drive intestinal stem cell progeny differentiation toward the absorptive enterocyte lineage in fed animals.

• Why it matters: Progenitor cells must connect nutrient-driven metabolism to fate decisions, but the specific signaling circuit that licenses differentiation during tissue renewal is unclear.
• What they did: The study mapped a nutrient-responsive pathway where PWP1, downstream of mTORC1, promotes Hedgehog signaling gene expression in high-mTORC1 progenitors, with feedback where elevated Hh inhibits mTORC1 and limits PWP1 nuclear localization.
• The result: Disrupting the mTORC1–PWP1–Hh axis causes progressive enterocyte turnover failure during aging and reduced lifespan, while barrier function persists and renewal defects deregulate intestinal metabolism.

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