Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Biol. Author manuscript; available in PMC Jan 5, 2007.
Published in final edited form as:
Curr Biol. Nov 7, 2006; 16(21): 2135–2142.
doi:  10.1016/j.cub.2006.08.086
PMCID: PMC1764209

Differential regulation of germline mRNAs in soma and germ cells by zebrafish miR-430


Early in development, primordial germ cells (PGCs) are set aside from somatic cells and acquire a unique gene expression program [1]. The mechanisms underlying germline-specific gene expression are largely unknown. Nanos expression is required during germline development [25] and posttranscriptionally restricted to PGCs [4, 6, 7, 8]. Here we report that the microRNA miR-430 targets the 3′ untranslated region (UTR) of nanos1 during zebrafish embryogenesis. A miR-430 target site within the nanos1 3′UTR reduces poly(A) tail length, mRNA stability and translation. Repression is disrupted in maternal-zygotic dicer mutants (MZdicer), which lack mature miRNAs [9], and restored by injection of processed miR-430. Although miR-430 represses other genes equally in germline and soma, specific regions in the nanos1 3′UTR compensate for microRNA-mediated repression in PGCs and allow germline-specific expression. We show that the 3′UTR of an additional PGC-specific gene, TDRD7, is also targeted by miR-430. These results indicate that miR-430 targets the 3′UTRs of germline genes and suggest that differential susceptibility to microRNAs contributes to tissue-specific gene expression.


nanos1 3′UTR induces mRNA deadenylation

Zebrafish nanos1 mRNA is maternally supplied to the early embryo [4]. Multiple post-transcriptional mechanisms function via the nanos1 3′UTR to ensure protein expression specifically in PGCs. First, nanos1 mRNA is localized to the germ plasm at the cleavage furrows [4, 10, 11]. Second, the nanos1 3′UTR represses nanos1 translation in somatic cells. Third, nanos1 mRNA is rapidly degraded in somatic cells but stably maintained in PGCs [4]. These mechanisms lead to protein expression specifically in PGCs [4, 12]. A GFP reporter mRNA containing the nanos1 3′UTR injected at the one-cell stage is stabilized in PGCs but is translationally repressed and degraded in somatic cells [4] (Fig.1A). We took advantage of this injection assay to elucidate the molecular basis of posttranscriptional regulation of nanos1.

Figure 1
The nanos1 3′UTR induces deadenylation

The poly(A) tail is a key determinant of mRNA stability and translation efficiency [1315]. We therefore asked if the post-transcriptional repression activity of the nanos1 3′UTR in somatic cells is mediated by the control of poly(A) tail length (Fig.1B). We compared the poly(A) tail dynamics of GFP-nanos1 mRNA to two control mRNAs that contained either GFP ORF alone (GFP mRNA) or GFP ORF with the vasa 3′UTR (GFP-vasa mRNA). We used the latter reporter, because the vasa 3′UTR restricts the mRNA to PGCs but does not repress protein synthesis in somatic cells as efficiently as the nanos1 3′UTR (Fig.1A and [16] ). This suggests that the nanos1 and vasa 3′UTRs mediate posttranscriptional regulation by different mechanisms. Analysis of the poly(A) tail dynamics revealed that GFP-nanos1 mRNA was initially polyadenylated but almost completely lost its poly(A) tail at 4–6 hour post fertilization (hpf). In contrast, GFP and GFP-vasa mRNA retained a ~150 nt poly(A) tail (Fig.1C). The injected GFP reporters recapitulated the poly(A) tail dynamics of endogenous nanos1 mRNA and vasa mRNAs (Fig.S1). These results indicate that the bulk of nanos1 mRNA lost its poly(A) tail during embryogenesis due to a sequence element within its 3′UTR. Similar results were obtained when the poly(A) tail was added in vitro prior to injection (Fig.1D), suggesting that the nanos1 3′UTR induces deadenylation and might also reduce de novo polyadenylation.

Deadenylation of nanos1 mRNA is not caused by translational repression

Deadenylation could be either the cause or the result of translational repression [17]. To distinguish between these possibilities, we analyzed the poly(A) length of GFP reporter mRNAs primed with A-cap. A-cap does not interact with the translation initiation factor eIF4E and inhibits translation initiation [18]. A-capped GFP mRNA was not translated in zebrafish embryos (Fig.S2A) and had the same poly(A) profile as the m7G-capped GFP mRNA (Fig.S2B, lower panel). Conversely, A-capped GFP-nanos1 mRNA was rapidly deadenylated, similarly to m7G-capped GFP-nanos1 mRNA (Fig.S2B, upper panel). These results indicate that deadenylation promoted by the nanos1 3′UTR is not caused by the lack of translation initiation and does not require active translation.

A short cis-regulatory element controls deadenylation and translational repression

To identify the cis-regulatory element within the nanos1 3′UTR required for deadenylation, we examined the poly(A) tail dynamics and GFP expression of a series of reporters that contained deletion mutants of the nanos1 3′UTR (Fig.2A). This analysis led to the identification of a 79-nucleotide (nt) deadenylation element (Ib). A GFP reporter mRNA bearing the fragment Ib underwent deadenylation and translational repression. Conversely, deletion of the fragment Ib from the nanos1 3′UTR (ΔIb) blocked rapid deadenylation and repression of the GFP reporter in somatic cells (Fig.2A, B and not shown). Thus, the fragment Ib is necessary and sufficient to induce rapid deadenylation and repress GFP reporter expression in somatic cells.

Figure 2
Identification of the deadenylation element

To identify the core sequence elements responsible for the rapid deadenylation, we used a series of mutants within region Ib (Fig.2C). Base-substitutions within regions D and E strongly inhibited deadenylation of the GFP reporter mRNA, whereas other substitutions only affected deadenylation weakly (B, F, G, and H) or had no effect (A, C, I, J and K) (Fig.2D). Concomitantly, repression of the GFP reporter was lost by substitutions D and E (Fig.2E and data not shown). These experiments indicate that the sequence elements D and E within the nanos1 3′UTR are necessary for the rapid deadenylation and repression of the GFP reporter in somatic cells.

MiR-430 induces deadenylation and translational repression in somatic cells

We hypothesized that a microRNA (miRNA) might bind to the D-E element and induce mRNA deadenylation and repression. Although their mechanism of action is not fully understood, miRNAs regulate target mRNA deadenylation [1921] and inhibit protein synthesis by repressing translation [2224]. We found that the sequence GCACUU in site D-E in the nanos1 3′UTR is complementary to nucleotides 2 to 7 of miR-430 (Fig.3A), the miRNA “seed” sequence important for target mRNA recognition [2528]. MiR-430 is expressed ubiquitously during early embryogenesis and required for normal morphogenesis during gastrulation and brain development [9]. To determine if miR-430 induces target deadenylation and repression through the D-E region in the nanos1 3′UTR, we used three approaches. First, we injected the GFP-nanos1 reporter into wild type, MZdicer mutants, and MZdicer mutants injected with miR-430 duplex (MZdicer+miR-430)(Fig.3B). The RNaseIII enzyme Dicer is required for miRNA processing, and loss of maternal and zygotic dicer (MZdicer) results in loss of mature miRNAs, including miR-430 [9]. We found that repression and deadenylation of the GFP-nanos1 reporter were reduced in MZdicer mutants. Conversely, injection of miR-430 duplex into MZdicer mutants restored regulation of the nanos1 reporter mRNA (Fig.3C and D). In contrast, expression of the GFP-vasa reporter, which does neither contain a GCACUUU sequence nor promote deadenylation, is similar in wild-type and MZdicer embryos (Fig.S4). Second, we mutated two nucleotides within the predicted target site that disrupt the pairing with the miR-430 seed (GCACUU to GGUCUU; Fig. 3A). We found that these mutations lead to higher GFP expression levels in somatic cells and delayed deadenylation compared to the wild-type reporter (Fig.3E and F). Third, we inserted three copies of the BCDE element downstream of the GFP ORF (3×BCDE) (Fig.3G and H). 3×BCDE recapitulated the deadenylation and repression activity of the nanos1 3′UTR, whereas a mutated BCDE sequence (GCACUU to GGUCUU, 3×BCDEmut) did not. Furthermore, co-injection of a mutant miR-430b duplex with compensatory mutations that basepair with BCDEmut restored deadenylation and repression. These experiments indicated that the BCDE site is a bona fide miR-430 target site and induces deadenylation and repression of the GFP reporter.

Figure 3
miR-430 mediates deadenylation and repression of protein synthesis induced by the nanos1 3′UTR

MiRNAs not only cause translational repression but also degradation of target mRNAs[19, 29, 30]. We therefore asked whether miR-430 is also responsible for the clearance of the GFP-nanos1 reporter mRNA ([4] and Fig.1A). In situ hybridization showed that GFP-nanos1 mRNA accumulates in somatic cells in the absence of miR-430 regulation (Fig.S4). These experiments indicate that miR-430 accelerates GFP-nanos1 mRNA decay in somatic cells.

Cis-elements within the nanos1 3′UTR allow protein expression in PGCs in the presence of miRNAs

The differential regulation of the nanos1 3′UTR by miR-430 contrasts with previous studies of miR-430 targets. In particular, miR-430 is uniformly expressed during early embryogenesis, and previously analyzed miR-430 target mRNAs and synthetic miR-430 reporters are repressed equally in somatic cells and PGCs [9, 19]. Indeed, in the absence of additional sequences from the nanos1 3′UTR, the 3×BCDE reporter was repressed in the soma and germline (Fig.3E and and4C).4C). Thus, miR-430 can be active both in the soma and PGCs, but the nanos1 3′UTR is more susceptible to repression in the soma. To determine the mechanistic basis for the differential repression by miR-430, we performed four experiments. First, we asked if differential susceptibility is unique to miR-430 or if other miRNAs act similarly. We replaced the miR-430 target site in the nanos1 3′UTR with a miR-204 imperfect target site (GFP-nanos1204 IPT mRNA). Injection of intermediate levels of the miR-204 duplex strongly repressed the GFP-nanos1204 IPT reporter in somatic cells but not in PGCs (Fig.4E). This experiment suggests that miRNAs have differential effects on the nanos1 3′UTR in the soma and germline. Second, we asked whether the location of the miR-430 target site within the nanos1 3′UTR affects its activity. We placed the miR-430 site at the 5′ or 3′end of the nanos1 3′UTR, 127 nt or 450 nt away from its original location (Fig.4A). The nanos1 3′UTR promoted protein synthesis in PGCs in the presence of the displaced miR-430 site. This result indicates that the local environment of the miR-430 site is not required for differential expression in the soma and germline (Fig.4F and G). Third, we determined if there are cis-elements in the nanos1 3′UTR that allow PGC expression in the presence of miR-430. We examined GFP expression of the nanos1 3′UTR deletion constructs in PGCs (Fig.2A and Fig.S3) and found that fragment Ib, which contains the miR-430 site, promoted GFP expression in PGCs. Similarly, the remainder of the nanos1 3′UTR (Δ1b) also promoted GFP expression in PGCs. Addition of the miR-430 site (ΔIb430IPT) showed that the ΔIb fragment directed protein synthesis in PGCs in the presence of miR-430 (Fig.S3). Hence, the nanos1 3′UTR contains at least two cis-regulatory regions that contribute to the differential repression in soma and germline. Fourth, we asked if the nanos1 3′UTR allows expression in PGCs by sequestering the target mRNA from miR-430. In this scenario (e.g. storage in a specific subcellular compartment), nanos1 reporter mRNA would be inaccessible to miRNAs in germ cells. To test this model, we introduced three copies of the miR-430 target site in the 3′UTR. Strikingly, this derivative of the nanos1 3′UTR was repressed by miR-430 in both PGCs and somatic cells (Fig.4H). Similarly, injection of high amounts of miR-204 inhibited the GFP expression of nanos1miR-204 mRNA in PGCs and somatic cells (data not shown). Taken together, these experiments indicate that the nanos1 3′UTR is accessible to miRNAs in PGCs and that the nanos1 3′UTR contains elements that allow the post-transcriptional activation in PGCs even in the presence of miR-430.

Figure 4
The nanos1 3′UTR allows protein expression in PGCs in the presence of miRNAs

The TDRD7 3′UTR is targeted by miR-430 and directs protein expression in PGCs

To determine if the regulation of germline genes by miR-430 is a general phenomenon, we asked whether miR-430 regulates the expression of other PGC-specific mRNAs. Using the ZFIN gene expression database (http://zfin.org), we found that zgc:56669, which encodes Tudor domain containing protein 7 (TDRD7), includes two GCACUU sequences in its 3′UTR. In situ hybridization showed that zgc:56669/TDRD7 is expressed maternally and restricted to PGCs, similar to nanos1 (Fig.5A-E and data not shown). Reporter assays revealed that the zgc:56669/TDRD7 3′UTR repressed protein synthesis in somatic cells, similar to the nanos1 3′UTR (Fig.5G). Two lines of evidence suggest that repression of GFP-zgc:56669/TDRD7 in somatic cells depends on miR-430. First, GFP expression of the TDRD7 reporter was higher in somatic cells that lack miR-430 (MZdicer mutants) than in wild-type embryos (Fig.5G and H). Second, mutations in the predicted target sites (Fig. 5F) abolished repression of the GFP reporter in somatic cells (Fig.5I and J). These results indicate that both the nanos1 and zgc:56669/TDRD7 3′UTRs mediate miR-430-induced repression in somatic cells.

Figure 5
The TDRD7 3′UTR is targeted by miR-430 in somatic cells and allows protein expression in PGCs


Our study indicates that miR-430 targets the 3′UTR of zebrafish nanos1 to induce mRNA deadenylation, mRNA degradation and translational repression in somatic cells (Fig.3). Conversely, the nanos1 3′UTR also includes cis-acting elements that allow activity in PGCs even in the presence of miRNA-mediated repression (Fig.4). Since another germline gene, TDRD7, is also targeted by miR-430, our results suggest that the differential effects of miR-430 in somatic cells and PGCs contribute to germline-specific gene expression.

While miR-430 is an important regulator of the nanos1 3′UTR, two observations suggest that there are additional mechanisms that regulate nanos1 expression. First, miR-430 is expressed at the onset of zygotic transcription (MBT) [9], whereas maternally provided GFP-nanos1 mRNA is posttranscriptionally repressed already prior to MBT [12]. Second, the degradation of endogenous nanos1 mRNA still occurs in MZdicer mutants (data not shown). Therefore we propose that miR-430 contributes to, but is not the sole determinant of the soma-specific decay and translational repression of nanos1 mRNA. Indeed, studies in Drosophila have shown that nanos mRNA is regulated by multiple post-transcriptional mechanisms including deadenylation, mRNA decay and translational repression [6, 3135].

Previous reporter studies have shown that miR-430 target mRNAs are equally susceptible to repression in somatic cells and PGCs [9, 19]. The results presented here identify a novel class of miR-430 targets that is differentially regulated between soma and germline. In the case of nanos1, differential repression is due to cis-acting elements in the 3′UTR. The exact role of these sequences is not known, but our study excludes several simple models. First, local masking of the miR-430 binding site is unlikely to be responsible for PGC-specific activation, because the nanos1 3′UTR can promote protein synthesis in PGCs independent of the sequence and location of the miRNA target site (Fig.4E, F and G). Second, it is unlikely that the nanos1 mRNA is sequestered from miR-430, because extra copies of the miR-430 target site make the nanos1 reporter susceptible to repression in PGCs (Fig.4H). Excluding these models, we speculate that PGCs promote the expression of nanos1 and other germline-specific mRNAs not by inactivation of the miRNA or its associated machinery but by recruiting other factors to the 3′UTR that increase mRNA stability or translation.

In addition to revealing a role for microRNAs in soma versus germline gene expression, our results have wider implications for the regulation of mRNAs by miRNAs. We found that miRNAs can be effective regulators of a target mRNA in one tissue but ineffective in another tissue. Hence, the presence of a miRNA target site and repression in one tissue (e.g. somatic cells) does not necessarily result in repression in another tissue (e.g. PGCs). Analogously, it has been shown that some miRNA targets have differential susceptibilities under stress and normal conditions [36]. Hence, miRNA-mediated regulation is conditional on tissue-specific or cell-state specific factors. Recent studies have also shown that some predicted miRNA targets are expressed at high levels in cells that express the cognate miRNA [19, 29, 37, 38]. These observations and our results suggest that there are not only “anti-targets”, which have evolved 3′UTRs that lack miRNA target sites [37, 38], but also “resistant targets”, which have evolved mechanisms to counteract the effects of miRNAs.

Supplementary Material



We thank members of our labs, especially T. Takasaki and K. Fukumura, for valuable discussions, the Yasuda lab members for help during the initial phase of the project, and H. Knaut for discussions and critical reading of the manuscript. This work was supported by Grants-in-Aid from MEXT and JSPS, and also supported in part by The Asahi Glass Foundation to K.I. Y.M was supported by JSPS Research Fellowships. A.J.G. was supported by EMBO and is currently supported by a Human Frontier Science Program fellowship. A.F.S. was an Irma T. Hirschl Trust Career Scientist and an established Investigator of the American Heart Association. This work was also supported by grants from the NIH (A.F.S).


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