Smaug

Abstract: Small RNAs of the piRNA (Piwi-associated RNA) class have various functions in the germline — repressing transposable elements, maintaining germline stem cells and promoting genome stability. Rouget et al. have now uncovered a function for piRNAs outside the germline, in the fruit fly embryo. Specifically, piRNAs that are complementary to a sequence in the 3′-untranslated region of an mRNA for the embryonic posterior morphogen Nanos facilitate adenylation of the mRNA and its subsequent decay. Without piRNAs, Nanos accumulates and developmental defects result. Piwi-associated RNAs (piRNAs) are small RNAs with several functions in the germline, such as repressing transposable elements and helping to maintain germline stem cells. Now, a function for piRNAs has been discovered outside the germline, in the fruitfly embryo. Specifically, piRNAs are required for the decay of the messenger RNA encoding the posterior morphogen Nanos. When piRNA-induced regulation is impaired, this mRNA is stabilized and developmental defects ensue. Piwi-associated RNAs (piRNAs), a specific class of 24- to 30-nucleotide-long RNAs produced by the Piwi-type of Argonaute proteins, have a specific germline function in repressing transposable elements. This repression is thought to involve heterochromatin formation and transcriptional and post-transcriptional silencing1,2,3,4,5,6. The piRNA pathway has other essential functions in germline stem cell maintenance7 and in maintaining germline DNA integrity8,9,10. Here we uncover an unexpected function of the piRNA pathway in the decay of maternal messenger RNAs and in translational repression in the early embryo. A subset of maternal mRNAs is degraded in the embryo at the maternal-to-zygotic transition. In Drosophila, maternal mRNA degradation depends on the RNA-binding protein Smaug and the deadenylase CCR411,12,13, as well as the zygotic expression of a microRNA cluster14. Using mRNA encoding the embryonic posterior morphogen Nanos (Nos) as a paradigm to study maternal mRNA decay, we found that CCR4-mediated deadenylation of nos depends on components of the piRNA pathway including piRNAs complementary to a specific region in the nos 3′ untranslated region. Reduced deadenylation when piRNA-induced regulation is impaired correlates with nos mRNA stabilization and translational derepression in the embryo, resulting in head development defects. Aubergine, one of the Argonaute proteins in the piRNA pathway, is present in a complex with Smaug, CCR4, nos mRNA and piRNAs that target the nos 3′ untranslated region, in the bulk of the embryo. We propose that piRNAs and their associated proteins act together with Smaug to recruit the CCR4 deadenylation complex to specific mRNAs, thus promoting their decay. Because the piRNAs involved in this regulation are produced from transposable elements, this identifies a direct developmental function for transposable elements in the regulation of gene expression.

Abstract: Translational regulation plays an essential role in development and often involves factors that interact with sequences in the 3′ untranslated region (UTR) of specific mRNAs. For example, Nanos protein at the posterior of the Drosophila embryo directs posterior development, and this localization requires selective translation of posteriorly localized nanos mRNA. Spatial regulation of nanos translation requires Smaug protein bound to the nanos 3′ UTR, which represses the translation of unlocalized nanos transcripts. While the function of 3′ UTR-bound translational regulators is, in general, poorly understood, they presumably interact with the basic translation machinery. Here we demonstrate that Smaug interacts with the Cup protein and that Cup is an eIF4E-binding protein that blocks the binding of eIF4G to eIF4E. Cup mediates an indirect interaction between Smaug and eIF4E, and Smaug function in vivo requires Cup. Thus, Smaug represses translation via a Cup-dependent block in eIF4G recruitment.