The Drosophila ecdysone receptor promotes or suppresses proliferation according to ligand level

The steroid hormone 20-hydroxy-ecdysone (20E) promotes proliferation in Drosophila wing precursors at low titer but triggers proliferation arrest at high doses. Remarkably, wing precursors proliferate normally in the complete absence of the 20E receptor, suggesting that low-level 20E promotes proliferation by overriding the default anti-proliferative activity of the receptor. By contrast, 20E needs its receptor to arrest proliferation. Dose-response RNA sequencing (RNA-seq) analysis of ex vivo cultured wing precursors identifies genes that are quantitatively activated by 20E across the physiological range, likely comprising positive modulators of proliferation and other genes that are only activated at high doses. We suggest that some of these “high-threshold” genes dominantly suppress the activity of the pro-proliferation genes. We then show mathematically and with synthetic reporters that combinations of basic regulatory elements can recapitulate the behavior of both types of target genes. Thus, a relatively simple genetic circuit can account for the bimodal activity of this hormone. [Display omitted] •The steroid hormone 20E has a bimodal effect on proliferation•Low-level 20E abrogates the default anti-proliferation activity of the 20E receptor•An additional transcription program activated by high 20E suppresses proliferation•Simple regulatory elements suffice to recapitulate the bimodal activity of 20E Perez-Mockus et al. show that the steroid hormone 20-hydroxy-ecdysone (20E) promotes or inhibits cell proliferation in a concentration-dependent manner. This bimodal activity relies on the activation of “high-threshold” target genes that override the pro-proliferation effect of low 20E concentrations.