Synthesis of the posterior determinant Nanos is spatially restricted by a novel cotranslational regulatory mechanism

Clark, Ira E.; Wyckoff, David; Gavis, Elizabeth R.

doi:10.1016/s0960-9822(00)00754-5

Cited by 92 publications

(85 citation statements)

References 16 publications

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“…However, it has been difficult to study the mechanism of regulation in detail because hb translational regulation has not been recapitulated faithfully in in vitro or tissue culture assays. Recently, a number of in vitro translation systems from Drosophila embryos have been established to study the regulation of nos and oskar mRNAs (30)(31)(32). Unfortunately, we have not been able to recapitulate hb regulation with these and similar systems (data not shown).…”

Section: Resultsmentioning

confidence: 89%

“…Although we cannot exclude the possibility that these transcripts are degraded in the eye primordia as a result of NRE-mediated removal of the poly(A) tail, it is intriguing to speculate that the NRE complex may act to directly interfere with the function of the general translation machinery on transcripts containing NREs. Interestingly, other maternal RNAs (e.g., oskar and nos) whose translational repression, like hb, is mediated by sequences in the 3Ј UTR, do not require the poly(A) tail for their regulation (30,50,51). This finding suggests that direct inhibition of the translation machinery may be a common strategy in the Drosophila embryo.…”

Section: Discussionmentioning

confidence: 99%

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Poly(A)-independent regulation of maternal hunchback translation in the Drosophila embryo

Chagnovich

Lehmann²

2001

Proc. Natl. Acad. Sci. U.S.A.

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Development of the Drosophila abdomen requires repression of maternal hunchback (hb) mRNA translation in the posterior of the embryo. This regulation involves at least four components: nanos response elements within the hb 3 untranslated region and the activities of Pumilio (PUM), Nanos (NOS), and Brain tumor. To study this regulation, we have developed an RNA injection assay that faithfully recapitulates the regulation of the endogenous hb message. Previous studies have suggested that NOS and PUM can regulate translation by directing poly(A) removal. We have found that RNAs that lack a poly(A) tail and cannot be polyadenylated and RNAs that contain translational activating sequences in place of the poly(A) tail are still repressed in the posterior. These data demonstrate that the poly(A) tail is not required for regulation and suggest that NOS and PUM can regulate hb translation by two mechanisms: removal of the poly(A) tail and a poly(A)-independent pathway that directly affects translation.

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Section: Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Poly(A)-independent regulation of maternal hunchback translation in the Drosophila embryo

Chagnovich

Lehmann²

2001

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, the association of Staufen 1 and Staufen 2 with polysomes observed in oligodendrocytes (this study) and in other cell systems Marion et al, 1999;Luo et al, 2002) is puzzling, because most polysomes are thought to be actively translating. Nevertheless, mechanisms for mRNA repression were described, in which the mRNA molecules are found in stalled-yet puromycin sensitive-polysomes that do not produce polypeptides (Clark et al, 2000, Ruegsegger et al, 2001. The presence of translationally repressed messengers in myelin Staufen granules remains to be confirmed.…”

Section: Staufen 1 Staufen 2 and The Major Targeted Mbp Mrnas Form mentioning

confidence: 99%

Staufen Recruitment into Stress Granules Does Not Affect Early mRNA Transport in Oligodendrocytes

Thomas

Tosar

Loschi

et al. 2005

MBoC

136

134

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INTRODUCTIONFrom the early steps of mRNA transport to the latest events of degradation, cytoplasmic RNA granules are highly relevant to the physiology of mRNA, including silencing and activation (reviewed in Wickens and Goldstrohm, 2003). Granules packaging targeted mRNAs appear in oligodendrocytes and other polarized vertebrate cells as dense structures, containing also ribosomes and with an average diameter of 1 m ( Barbarese et al., 1995;Barry et al., 1996;Ainger et al., 1997;Knowles and Kosik, 1997;Carson et al., 2001;Krichevsky and Kosik, 2001). A different type of RNA granules known as stress granules (SGs) appears transiently upon induction of cellular stress. SGs are large ribonucleoparticles (RNPs) and are thought to be in dynamic equilibrium with translating polysomes (Kedersha et al., 2000Anderson and Kedersha, 2002).The double-stranded RNA-binding protein Staufen emerges as a relatively ubiquitous RNA granule-forming factor (Ferrandon et al., 1994;Duchaine et al., 2000; Kiebler and DesGrosseillers, 2000;Micklem et al., 2000). This protein was initially described in Drosophila oocytes, where it is found in granules involved in microtubule-dependent localization of maternal mRNAs to define the anterior-posterior axis of the embryo (Lasko, 1999;Kloc et al., 2002). Staufen is recruited into granules upon its interaction with bicoid mRNA 3ЈUTR sequences that mediate targeting of the messenger, and it is strictly required for the formation of these granules (Ferrandon et al., 1994(Ferrandon et al., , 1997. Likewise, the positioning of oskar mRNA at the oocyte posterior pole involves the formation of Staufen-containing granular structures known as polar bodies (Lasko, 1999;Kloc et al., 2002). Staufen also participates in actin-dependent segregation of prospero mRNA during asymmetric division of embryonic CNS cells (reviewed in Lasko, 1999; Kiebler and DesGrosseillers, 2000;Kloc et al., 2002). Moreover, Drosophila Staufen is essential for long-term memory acquisition, a phenomenon known to require mRNA targeting followed by local translation at the synapse (Dubnau et al., 2003).Two homologous genes, Staufen 1 and Staufen 2, were reported in mammalians and amphibians (Kiebler and DesGrosseillers, 2000;Monshausen et al., 2001;Tang et al., 2001;Kress et al., 2004;Yoon and Mowry, 2004 et al., , Kohrmann et al., 1999Macchi et al., 2003). Rat Staufen 1 binds to the dendrite targeting element (DTE) of MAP2 mRNA (Monshausen et al., 2001) and, in addition, Staufen 1 RNPs isolated from brain and cortical neurons contain localized RNAs and associate to motor molecules (Krichevsky and Kosik, 2001;Ohashi et al., 2002;Mallardo et al., 2003;Kanai et al., 2004). Furthermore, overexpression of a truncated form of Staufen 2 leads to a reduction of the dendritic RNA content (Tang et al., 2001). Likewise, interference strategies in amphibian oocytes indicates that Xenopus Staufen 1 is involved in the late localization pathway to the vegetal pole (Kress et al., 2004;Yoon and Mowry, 2004). In this study, we investigated the dist...

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“…For proper embryonic development, 4% of Nanos mRNAs are exclusively localized to the posterior pole of the Drosophila embryo, whereas the remaining 96% of unlocalized mRNAs must be translationally repressed elsewhere (Gavis and Lehmann 1994); the repression is mediated by an element at the 3´UTR. These unlocalized Nanos mRNAs are associated with polyribosomes in a puromycin-sensitive manner (Clark et al 2000). Interestingly, the Nanos mRNA-associated polyribosomes are capable of completing the elongation phase of the translation cycle in in vitro extracts made from a specific embryo strain where the mRNAs are all unlocalized and translationally repressed.…”

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confidence: 99%

Function and Localization of MicroRNAs in Mammalian Cells

Leung¹,

Sharp²

2006

Cold Spring Harbor Symposia on Quantitative Biology

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The miRNAs are a class of noncoding RNAs found in animals and plants, whose mature products are approximately 21-22 nucleotides in length (Bartel 2004;Kim 2005). These RNAs are predicted to regulate about 30% of mammalian mRNAs through interactions with their 3´UTRs (untranslated regions) Rajewsky 2006). The binding of miRNAs can result in translational repression and/or degradation of mRNAs Valencia-Sanchez et al. 2006). We discuss here the various functions of miRNAs and their possible cytoplasmic locale in mammalian cells. MIRNA-MEDIATED TRANSLATIONAL REPRESSIONThe role of miRNA was first demonstrated as the translational repressor by its founding member lin-4 in the nematode Caenorhabditis elegans (Lee et al. 1993;Wightman et al. 1993). Genetic analysis showed that the gene product of lin-4 acted as a negative regulator of LIN-14 expression after larval stage L1, and the 3´UTR of the lin-14 mRNA was required for this regulation (Arasu et al. 1991). After the discovery of the gene product of lin-4 as a 22-nucleotide RNA and the potential binding sites at the 3´UTR of lin-14 mRNA, the miRNA:mRNA base-pairing was realized to be crucial in regulating lin-14 expression (Lee et al. 1993;Wightman et al. 1993). The 3´UTR of lin-14 mRNAs contains seven lin-4 miRNA-binding sites, which are conserved in Caenorhabditis briggsae. lin-14 mRNAs with mutations in all of these binding sites can no longer be down-regulated by lin-4 (Ha et al. 1996). It was initially found that the steady-state level of lin-14 transcript was not reduced more than twofold by the lin-4 (although a recent report detected a fivefold reduction; Bagga et al. 2005; and see below), whereas its protein level was reduced by approximately tenfold from larval stage L1 to L2 (Olsen and Ambros 1999). Furthermore, neither the transcription rate nor the status of polyadenylation for lin-14 mRNA changed from L1 to L2 (Olsen and Ambros 1999). This evidence points to the role of lin-4 as a translational repressor of lin-14 mRNA.The mechanisms by which lin-4 suppresses the expression of lin-14 mRNA were investigated. Biochemical analysis suggested that both lin-4 miRNA and lin-14 mRNA cosedimented with polyribosomes (Olsen and Ambros 1999). A similar polyribosomal association of miRNA is also observed in mammalian cells (Kim et al. 2004;Nelson et al. 2004;Petersen et al. 2006). However, another substantial fraction of miRNAs do not cosediment with the polyribosomes, but with a fraction slower than monosomes (Nelson et al. 2004). This more slowly sedimenting fraction is typically devoid of target mRNA, probably representing miRNA-containing ribonucleoparticles (miRNPs) in excess to target mRNAs or those miRNAs that dissociated from their target mRNAs during isolation. Evidence showing that the polyribosome-associated miRNA target mRNAs are engaged in some form of active translation has been reported, for example, human K-ras and lin-28 mRNAs that are targeted by let-7 miRNA (Nelson et al. 2004; Maroney et al., this volume) or a model luciferase mRNA targeted by a...

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Synthesis of the posterior determinant Nanos is spatially restricted by a novel cotranslational regulatory mechanism

Cited by 92 publications

References 16 publications

Poly(A)-independent regulation of maternal hunchback translation in the Drosophila embryo

Poly(A)-independent regulation of maternal hunchback translation in the Drosophila embryo

Staufen Recruitment into Stress Granules Does Not Affect Early mRNA Transport in Oligodendrocytes

Function and Localization of MicroRNAs in Mammalian Cells

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