Control of antagonistic components of the hedgehog signaling pathway by microRNAs in Drosophila.
Hedgehog (Hh) signaling is critical for many developmental processes and for the genesis of diverse cancers. Hh signaling comprises a series of negative regulatory steps, from Hh reception to gene transcription output. We previously showed that stability of antagonistic regulatory proteins, including the coreceptor Smoothened (Smo), the kinesin-like Costal-2 (Cos2), and the kinase Fused (Fu), is affected by Hh signaling activation. Here, we show that the level of these three proteins is also regulated by a microRNA cluster. Indeed, the overexpression of this cluster and resulting microRNA regulation of the 3'-UTRs of smo, cos2, and fu mRNA decreases the levels of the three proteins and activates the pathway. Further, the loss of the microRNA cluster or of Dicer function modifies the 3'-UTR regulation of smo and cos2 mRNA, confirming that the mRNAs encoding the different Hh components are physiological targets of microRNAs. Nevertheless, an absence of neither the microRNA cluster nor of Dicer activity creates an hh-like phenotype, possibly due to dose compensation between the different antagonistic targets. This study reveals that a single signaling pathway can be targeted at multiple levels by the same microRNAs.
Friggi-Grelin
Florence
F
Institut de Recherches Signalisation, Biologie du Développement et Cancer, Université de Nice-Sophia Antipolis, CNRS UMR 6543, Centre de Biochimie, Parc Valrose, 06108 Nice Cedex 2, France.
Lavenant-Staccini
Laurence
L
Therond
Pascal
P
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D040461:Gene Components; D005786:Gene Expression Regulation / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D017403:In Situ Hybridization; D016547:Kinesins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D000072086:Smoothened Receptor; D014921:Wings, Animal / Q000033:anatomy & histology
D017931:DNA Primers; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D035683:MicroRNAs; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; C107452:cos protein, Drosophila; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; C085770:fu protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins