Genetics, Vol. 179, 429-439, May 2008, Copyright © 2008
doi:10.1534/genetics.107.083733

Control of Antagonistic Components of the Hedgehog Signaling Pathway by microRNAs in Drosophila

Florence Friggi-Grelin, Laurence Lavenant-Staccini and Pascal Therond1

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

1 Corresponding author: Institute of Signaling, Developmental Biology, and Cancer Research, Université de Nice-Sophia Antipolis, CNRS, UMR 6543, Centre de Biochimie, Parc Valrose, 6108 Nice Cedex 2, France.
E-mail: therond{at}unice.fr

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.