Control of a Metamorphic Switch

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When a single hormone--such as the steroid hormone ecdysone in insects--can cause a metamorphic reorganization of the organism from a larva to a pupa or from the pupal stage to the adult form, accidental activation of its signaling could be a catastrophe. Varghese and Cohen present findings showing that a microRNA-mediated feedback loop appears to help form a reliable switch mechanism for activating ecdysone signaling. The authors noted that the Drosophila gene encoding the ecdysone receptor contains predicted binding sites for the microRNA miR-14 . In transfected cells, expression of miR-14 inhibited expression of a reporter construct containing the ecdysone receptor promoter sequence. Mutant flies lacking miR-14 showed increased abundance of the ecdysone receptor, and some of the defects in miR-14 mutants were alleviated in flies in which one functional copy of the ecdysone receptor gene was removed. Thus, miR-14 appears to limit expression of the ecdysone receptor. Experiments with explanted larval fat bodies indicated that ecdysone increased the abundance of mRNA encoding the ecdysone receptor, an effect that was lost in cells depleted of the ecdysone receptor by RNAi (the primary transcript from the ecdysone receptor gene was not affected by the RNAi construct, so its abundance could be measured to estimate transcriptional activity of the gene). Furthermore, treatment of explants with ecdysone decreases the abundance of miR-14 , again with a requirement for the ecdysone receptor. The authors interpret these findings in light of the dramatic all-or-none biological effects of ecdysone. The hormone itself participates in a positive feedback loop by promoting transcription of the ecdysone receptor gene. Expression of the ecdysone receptor gene is normally opposed by miR-14 , but expression of miR-14 is also subject to repression by ecdysone signals. Thus, noise in the system--in the form of a transient increase in ecdysone receptor expression--may be buffered by the need to overcome miR-14 -mediated repression of ecdysone signaling. A more sustained activation of ecdysone signaling that lasts long enough for the decay of existing miR-14 is expected to exceed this threshold and release full activation of the self-sustaining ecdysone transcriptional autoregulatory loop. J. Varghese, S. M. Cohen, MicroRNA miR-14 acts to modulate a positive autoregulatory loop controlling steroid hormone signaling in Drosophila . Genes Dev. 21 , 2277-2282 (2007). [Abstract] [Full Text]