dDOR is an EcR coactivator that forms a feed-forward loop connecting insulin and ecdysone signaling.
BACKGROUND
Mammalian DOR was discovered as a gene whose expression is misregulated in muscle of Zucker diabetic rats. Because no DOR loss-of-function mammalian models are available, we analyze here the in vivo function of DOR by studying flies mutant for Drosophila DOR (dDOR).


RESULTS
We show that dDOR is a novel coactivator of ecdysone receptor (EcR) that is needed during metamorphosis. dDOR binds EcR and is required for maximal EcR transcriptional activity. In the absence of dDOR, flies display a number of ecdysone loss-of-function phenotypes such as impaired spiracle eversion, impaired salivary gland degradation, and pupal lethality. Furthermore, dDOR knockout flies are lean. We find that dDOR expression is inhibited by insulin signaling via FOXO.


CONCLUSIONS
This work uncovers dDOR as a novel EcR coactivator. It also establishes a mutual antagonistic relationship between ecdysone and insulin signaling in the fly fat body. Furthermore, because ecdysone signaling inhibits insulin signaling in the fat body, this also uncovers a feed-forward mechanism whereby ecdysone potentiates its own signaling via dDOR.
Francis
Víctor A
VA
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg, Germany.
Zorzano
Antonio
A
Teleman
Aurelio A
AA
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development*; D004440:Ecdysone / Q000378:metabolism*; D005216:Fat Body / Q000378:metabolism; D040461:Gene Components; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D055786:Gene Knockout Techniques; D007328:Insulin / Q000378:metabolism*; D008675:Metamorphosis, Biological / Q000502:physiology; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011987:Receptors, Steroid / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D004268:DNA-Binding Proteins; C104790:DOR protein, Drosophila; D029721:Drosophila Proteins; D007328:Insulin; D011987:Receptors, Steroid; C055469:ecdysone receptor; D004440:Ecdysone