The Francis Crick Institute, London NW1 1AT, UK.
The Francis Crick Institute, London NW1 1AT, UK.
Dev Cell. 2023 Oct 23;58(20):2128-2139.e4. doi: 10.1016/j.devcel.2023.08.032. Epub 2023 Sep 27.
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.
甾醇激素 20-羟基蜕皮甾酮（20E）在低浓度时促进果蝇翅原基的增殖，但在高浓度时会引发增殖停滞。值得注意的是，在完全缺乏 20E 受体的情况下，翅原基仍能正常增殖，这表明低水平的 20E 通过超越受体的默认抗增殖活性来促进增殖。相比之下，20E 需要其受体来阻止增殖。对离体培养的翅原基进行的剂量反应 RNA 测序（RNA-seq）分析鉴定出了在生理范围内被 20E 定量激活的基因，这些基因可能包括增殖的正调节剂以及仅在高剂量时才被激活的其他基因。我们推测，其中一些“高阈值”基因主要抑制了促增殖基因的活性。然后，我们通过数学和合成报告基因证明，基本调控元件的组合可以再现这两种类型靶基因的行为。因此，相对简单的遗传电路可以解释这种激素的双峰活性。
