Despite their fundamental importance for body size regulation, the mechanisms that stop growth are poorly understood. In Drosophila melanogaster, growth ceases in response to a peak of the molting hormone ecdysone that coincides with a nutrition-dependent checkpoint, critical weight. Previous studies indicate that insulin/insulin-like growth factor signaling (IIS)/Target of Rapamycin (TOR) signaling in the prothoracic glands (PGs) regulates ecdysone biosynthesis and critical weight. Here we elucidate a mechanism through which this occurs. We show that Forkhead Box class O (FoxO), a negative regulator of IIS/TOR, directly interacts with Ultraspiracle (Usp), part of the ecdysone receptor. While overexpressing FoxO in the PGs delays ecdysone biosynthesis and critical weight, disrupting FoxO–Usp binding reduces these delays. Further, feeding ecdysone to larvae eliminates the effects of critical weight. Thus, nutrition controls ecdysone biosynthesis partially via FoxO–Usp prior to critical weight, ensuring that growth only stops once larvae have achieved a target nutritional status.

Real-Time PCR finalReal-Time PCR quantification of E74B, phm and dibEcdysone quantification finalEcdysone quantifications for P0206>, >FoxO, P0206>FoxO and P0206>FoxO NK. All genotypes are in a FoxO null background.Final weight allPharate adult weights for males and females in all genotypes examined.CWData&Scripts