View Program - 63rd Annual Drosophila Research Conference

Approximately 50% of all cancer patients develop cachexia, a devastating wasting syndrome. This figure increases up to 80% in patients with advanced cancers. In recent years, a number of Drosophila cachexia models have been established, however, steroid hormone level changes, a frequent symptom of cachexia in patient, has remained insufficiently understood. We demonstrate here that the BTB zinc-finger transcription factor fruitless (fru) is a key player of steroid hormone signals and negatively regulates the synthesis of ecdysone in prothoracic gland (PG) cells by responding to steroid hormone levels in the body. Specifically, we show that Fru oscillates within the PG cells: a high concentration of Fru in the nuclei is concomitant with low-titer ecdysone levels in the body, and the protein is absent from PG nuclei at developmental stages when high-titer ecdysone pulses occur. Depletion of Fru in the PG accelerates larval development by causing precocious ecdysone signaling and a failure to repress ecdysone pulses. In contrast, excessive Fru expression in the PG arrests development that can be rescued by administrating an active ecdysteroid, and we show that Fru inhibits the ecdysteroid biosynthesis pathway by regulating Halloween genes. Notably, we show that this regulation has implications for the cachexia model. Fru in PG nuclei of cachexic larvae is maintained at a high level, and the periodicity of Fru expression associated with normal development is abolished, thereby maintaining a low level of circulating steroids in cachexic larvae. These findings suggest that aberrant expression of Fru in PG is a major reason for hormone imbalance in cachexic larvae and is partially responsible for the cachexia phenotype, thus provide a theoretical basis for hormone treatment of cachexia.

fruitless Controls the Timing of Steroid Hormone Pulses in Drosophila Somatic Cell