The generation of a zygote through fertilization marks the onset of development for the offspring, and requires the proper completion of sperm and oocyte development in the respective parents. Spermatogenesis produces haploid sperm capable of penetrating the oocyte, whereas oogenesis produces differentiated oocytes that are stockpiled with maternal nutrients, proteins, and mRNAs, and have outer layers that protect the embryo and enable fertilization. In most animals the oocyte is arrested in meiosis, and fertilization leads to initiation of mitosis as the oocyte nucleus completes meiosis and fuses with the haploid sperm nucleus. Fertilization also leads to changes in mRNA translation and protein stability, which support a period of development driven off of maternal stockpiles. After this initial stage of maternal control, which lasts for 1–2 mitotic divisions in mammals and 13 mitotic divisions in Drosophila, widespread transcription begins from the zygotic nuclei (Tadros and Lipshitz, 2009).

The production of viable offspring requires three key developmental events: oocyte maturation, the oocyte-to-embryo transition (OET), and the maternal-to-zygotic transition (MZT) (Figure 1A). Oocyte maturation involves the release of the primary meiotic arrest at prophase I and progression of the oocyte nucleus into meiotic divisions to produce a mature oocyte (egg) capable of being fertilized (Von Stetina and Orr-Weaver, 2011). The mature oocyte is arrested in metaphase II in most vertebrates and metaphase I in insects. The OET requires egg activation, which is coupled to fertilization in most animals. Egg activation releases the secondary meiotic arrest, allowing completion of meiosis (Horner and Wolfner, 2008). The MZT marks the transfer of control of development from the mother to the zygote as maternal mRNAs are degraded, transcription from the zygotic genome begins, and embryonic development becomes dependent on zygotic gene products (Tadros and Lipshitz, 2009). In Xenopus, zebrafish, and Drosophila the major activation of zygotic transcription occurs as the cell cycle lengthens and gastrulation begins, a developmental period referred to as the midblastula transition.

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In nearly all animals, oocyte maturation and the OET occur in the absence of transcription, and thus any changes in protein levels must occur through posttranscriptional regulatory mechanisms. Indeed, widespread changes in protein levels without corresponding changes in mRNA levels are observed at these developmental transitions (Kronja et al., 2014a, 2014b). Posttranscriptional regulation of gene expression during oocyte maturation, the OET, and early embryogenesis faces unique challenges, including stably storing maternal mRNAs through the prolonged periods of oogenesis and maintaining some of these mRNAs in a translationally inactive state (referred to as masking) while selectively translating others at the proper times in development. During mouse oocyte maturation ~1300 mRNAs are translationally upregulated and ~1500 are translationally downregulated (Chen et al., 2011). Similarly, during Drosophila egg activation ~1000 mRNAs are translationally upregulated, and ~500 are translationally repressed (Kronja et al., 2014b).

One long-appreciated mechanism of translational regulation during development acts through control of mRNA poly(A)-tail length (Richter, 2007; Weill et al., 2012). The observation of short poly(A) tails in oocytes from amphibians and marine invertebrates led to the proposal that short poly(A) tails help mask maternal mRNAs, preventing translation without triggering the destabilization that typically results from deadenylation. Specific mRNAs are then targeted for cytoplasmic polyadenylation, and the lengthened poly(A) tails in turn cause translational upregulation of these mRNAs (McGrew et al., 1989), as demonstrated for the mRNAs for c-mos and several cyclin genes during oocyte maturation in Xenopus (Sheets et al., 1994; Barkoff et al., 1998). The Cytoplasmic Polyadenylation Element Binding Protein (CPEB) plays a critical role in controlling translation of maternal mRNAs, both in recruiting Maskin to repress translation and later in promoting polyadenylation by binding cytoplasmic poly(A) polymerase together with Cleavage and Polyadenylation Specificity Factor (CPSF) (Richter, 2007; Weill et al., 2012; Ivshina et al., 2014). In Drosophila, the cytoplasmic poly(A) polymerase encoded by the wispy gene promotes poly(A)-tail lengthening during both oocyte maturation and egg activation (Benoit et al., 2008; Cui et al., 2008, 2013), and increased poly(A)-tail lengths of mRNAs for cyclin B, cortex, bicoid, torso, and Toll coincide with the translational upregulation of these mRNAs (Salles et al., 1994; Lieberfarb et al., 1996; Vardy and Orr-Weaver, 2007a; Benoit et al., 2008). Moreover, appending synthetic poly(A) tails of increasing lengths to the bicoid mRNA promotes the translation of this mRNA, which demonstrates a causal relationship between increased poly(A)-tail length and increased translation in early Drosophila embryos (Salles et al., 1994).

Translational repressors, some of which have been identified through genetic analysis of pattern formation in the Drosophila embryo, also act during oogenesis and early embryogenesis (Vardy and Orr-Weaver, 2007b; Besse and Ephrussi, 2008; Barckmann and Simonelig, 2013). These repressors can impact either poly(A)-tail length (Temme et al., 2014), the translational machinery, or both. Brain Tumor and Pumilio (PUM) bind to target mRNAs and recruit the CCR4-NOT deadenylase complex, which shortens poly(A) tails (Kadyrova et al., 2007; Temme et al., 2010; Newton et al., 2015). Bruno binds to target mRNAs during oogenesis and recruits the eIF4E-binding protein Cup, which represses translation by both blocking the interaction between eIF4E and eIF4G (Nakamura et al., 2004) and promoting deadenylation while repressing decapping, which traps mRNAs in a translationally repressed state (Igreja and Izaurralde, 2011). Similarly, the RNA-binding protein Smaug (SMG) is reported to recruit either Cup or the CCR4-NOT deadenylase complex, with the consequent repression of translation (Nelson et al., 2004; Semotok et al., 2005). smg mRNA is translationally repressed in the mature oocyte by PUM, and at egg activation this repression is relieved by the PAN GU (PNG) protein kinase complex (Tadros et al., 2007). PNG is also thought to regulate other translational regulators.

mRNA expression arrays, RNA-seq and ribosome-footprint profiling have enabled global analyses of mRNA levels and relative translational efficiencies (TEs) in Drosophila oocytes and embryos (Qin et al., 2007; Dunn et al., 2013; Chen et al., 2014; Kronja et al., 2014b). Measuring poly(A)-tail lengths has been more challenging due to the homopolymeric nature of the tail, and this technical hurdle has restricted studies to measuring tail lengths of a small number of Drosophila mRNAs (Salles et al., 1994; Lieberfarb et al., 1996) or to estimating relative differences in tail lengths more broadly using hybridization-based methods (Cui et al., 2013). However, methods are now available to measure poly(A)-tails of essentially any length for millions of individual mRNA molecules (Chang et al., 2014; Subtelny et al., 2014). In zebrafish and Xenopus, high-throughput measurements demonstrate that poly(A)-tail length and TE are globally coupled during early embryonic development (Subtelny et al., 2014), as expected from single-gene studies (McGrew et al., 1989; Sheets et al., 1994; Lieberfarb et al., 1996; Barkoff et al., 1998; Pesin and Orr-Weaver, 2007; Benoit et al., 2008). Surprisingly, however, this coupling disappears at gastrulation and is not observed in any of the post-embryonic samples examined (Subtelny et al., 2014). Thus, soon after a developmental shift in transcriptional control (the MZT), these vertebrate species undergo a developmental shift in translational control, in which TE abruptly changes from being strongly coupled to tail length to being uncoupled.

Drosophila melanogaster affords the opportunity to define changes in poly(A)-tail length and TE during oocyte maturation, the OET, and the MZT, facilitated by the high quality of both the genome assembly and the coding-sequence (CDS) annotations, the wealth of knowledge on regulatory proteins active during early development, the availability of genetic mutants in these known regulatory proteins, and the ability to isolate sufficient quantities of oocytes and embryos at distinct developmental stages for high-throughput sequencing techniques. Here we systematically analyze changes in poly(A)-tail length and TE during oocyte maturation, the OET and the MZT, and delineate the roles of Wispy, PNG, and SMG in regulating translation during these crucial periods. These studies reveal fundamental insights into the regulatory mechanisms and regimes operating during these key developmental transitions.

Our results from Drosophila oocytes and embryos increase the number of cellular environments known to possess global coupling between poly(A)-tail length and TE, which now include several stages of Drosophila oocytes as well as Drosophila, zebrafish, and Xenopus embryos prior to the onset of gastrulation. At least as early as the primary meiotic arrest point, changes in poly(A)-tail length largely explain changes in TE, and this regulatory strategy continues through early embryonic development. A switch around the onset of gastrulation uncouples poly(A)-tail length and TE in Drosophila, mirroring the developmental timing of the same uncoupling in zebrafish and Xenopus embryos. The uncoupling of TE from poly(A)-tail length is thus a broadly conserved developmental switch in the nature of translational control, occurring around the onset of gastrulation in both vertebrate and invertebrate embryos.

Changing the length of a poly(A) tail would influence both the number of poly(A)-binding proteins (PABPs) that could bind the tail and the probability that at least one PABP would be bound, with the former being more relevant in conditions of saturating PABP and the later being more relevant in conditions in which tails are competing for PABP. If the number of PABPs that bind the tail were most relevant, then TE changes might have correlated better with absolute tail-length changes than with relative tail-length changes. However, repeating our analyses using absolute tail-length changes rather than tail-length log₂ fold changes yielded the same results for the respective comparisons, with nearly identical R_s values (Figure 7—figure supplement 2), suggesting that PABP is limiting in the developmental stages in which tail length and TE are coupled, such that mRNAs are competing for PABP.

We presume that the correlation between poly(A)-tail length and TE that we observed in oocytes and pre-gastrulation embryos reflects a causal relationship, i.e., that changes in poly(A)-tail length at least partially cause the corresponding changes in TE. The other possibilities are that changes in TE cause changes in tail length or that these two measurements merely correlate without having a causal relationship. Because previous single-gene studies clearly demonstrate a causal role for cytoplasmic polyadenylation, and poly(A)-tail length itself, in regulating the translation of mRNAs during these developmental times (McGrew et al., 1989; Salles et al., 1994; Barkoff et al., 1998), we interpret our observation of a global correlation between poly(A)-tail length and TE as reflecting a causal relationship between the two wherein tail-length changes cause TE changes. Given this interpretation, our results indicate that widespread changes in poly(A)-tail length broadly reshape the translational profiles of oocytes and early embryos.

Despite this strong qualitative conclusion, we cannot provide quantitative estimates of the proportion of each TE change that is attributable to each tail-length change, as additional translational regulatory mechanisms presumably act to reinforce or oppose the effects of tail-length–dependent translational regulation. Indeed, we suspect that tail-length–independent processes often act concordantly with tail-length–dependent processes and thereby amplify the apparent effects of tail-length changes. Such amplification would explain why some mRNAs, including cyclin B, cyclin B3, fizzy, zelda, stat92E, bicoid, and torso, undergo translational activation that seems out of proportion to their tail-length changes.

A primary motivation for using Drosophila in our study was the opportunity to examine the impact of Wispy, PNG, and SMG on poly(A)-tail length and TE. Of particular interest was Wispy, the cytoplasmic poly(A) polymerase that acts during late oogenesis and early embryogenesis, and is essential for the OET (Benoit et al., 2008; Cui et al., 2008). Analysis of wispy mutants revealed key insights into both the mechanism of translational activation and the importance of tail shortening (as opposed to tail lengthening) in specifying translational control in Drosophila maturing oocytes and early embryos. Although poly(A)-tail lengths were typically shorter in wispy-mutant stage 13 oocytes and laid eggs compared to the corresponding wild-type samples, tail length and TE were coupled in both of these wispy-mutant contexts, and the relative changes in poly(A)-tail lengths during the OET in wild-type samples were largely preserved in the wispy-mutant samples, as were the changes in TE. Thus, the act of cytoplasmic polyadenylation is not necessary for the coupling of poly(A)-tail length to translation. Moreover, cytoplasmic polyadenylation is largely dispensable for specifying which mRNAs are to be translationally activated or repressed, implying that in Drosophila, selective deadenylation is more important for imparting this specificity. This greater importance for deadenylation does not preclude a role for selective cytoplasmic polyadenylation in translational control in Drosophila—differences were observed when comparing TE changes in wild-type and wispy-mutant samples (Figure 5D), and when comparing RPF measurements between wild-type and wispy-mutant samples (Figure 5—figure supplement 1D), including for cortex, a critical OET regulator. However, the greater importance of selective deadenylation for specifying translational control in Drosophila differs from the prevailing paradigm of vertebrates, which centers on selective cytoplasmic polyadenylation of mRNAs with cytoplasmic polyadenylation elements (Piqué et al., 2008; Weill et al., 2012). This suggests either a fundamental difference between invertebrates and vertebrates or that an underappreciated component of translational control in vertebrates occurs through more global cytoplasmic polyadenylation with selective deadenylation.

Despite the surprisingly modest perturbation of translational regulation that we observed in wispy-mutant laid eggs during egg activation, these laid eggs are blocked at the OET because of defective progression through meiosis and failure of pronuclei to fuse (Benoit et al., 2008; Cui et al., 2008). Why does this developmental arrest occur if translational regulation is largely preserved during egg activation in wispy mutants? One possibility is that the absolute level of translation in wispy-mutant eggs is reduced such that they make an inadequate amount of one or more essential protein. The other possibility rests on the observation that although TE changes and RPFs were remarkably concordant in the wispy-mutant and wild-type samples, they were not identical, and thus an aberrant change in expression for one or more key factor, such as cortex, might be sufficient to trigger the developmental arrest of wispy-mutant laid eggs.

Activity of the PNG kinase during egg activation affects most mRNAs that undergo translational activity changes at this developmental transition, both those that are up- and downregulated (Kronja et al., 2014b). Although the direct targets of PNG kinase remain to be identified, PNG is required to relieve the repressive effects of PUM (Vardy and Orr-Weaver, 2007a) and thereby derepresses translation of smg and other mRNAs (Tadros et al., 2007). In wild-type activated eggs the mRNAs dependent on PNG for translational up- or downregulation exhibited corresponding increases or decreases in poly(A)-tail length, and these tail-length changes did not occur in png mutants. Thus, for both translationally activated and translationally repressed mRNAs, the downstream effectors of PNG appear to regulate translation primarily through changes in poly(A)-tail length.

Translational repressors in addition to SMG have been proposed to contribute to PNG-dependent regulation (Tadros et al., 2007). Our results are consistent with the idea that PNG activates at least one additional translational repressor, as the set of mRNAs dependent on PNG for their translational downregulation were still somewhat translationally repressed and deadenylated relative to all other mRNAs in smg-mutant embryos, although less than in wild-type embryos. Additionally, although SMG is reported to act partly through a mechanism that does not involve deadenylation (Nelson et al., 2004; Semotok et al., 2005), essentially all the derepression observed in the smg-mutant embryos was accompanied by tail-length increases. Perhaps at other times SMG causes direct translational repression, but in 0–1 hr embryos it seems to act predominantly through deadenylation.

Within the overall framework in which tail-length changes cause the up- or downregulation of mRNAs for a vast repertoire of different genes, we discovered unanticipated complexities and exceptions. One unanticipated complexity was the evidence for tail-length–independent processes that appear to amplify the tail-length–dependent effects, as already discussed. Additional unanticipated complexity was observed during oocyte maturation, in which surprisingly diverse patterns of regulatory dynamics produce the ultimate changes in TE. Single-gene studies in Xenopus, which show that c-mos mRNA becomes polyadenylated and translated prior to the mRNAs for several cyclin B genes (Richter, 2007; Piqué et al., 2008), hint that the complex landscape of translational control observed in Drosophila extends to vertebrate oocyte maturation. The diverse temporal behaviors of translational regulation during oocyte maturation might reflect the evolving demands on the maturing oocyte, or perhaps simply differences in the timing of expression of RNA-binding proteins that interact with these different sets of mRNAs. Regardless, the observation of different temporal patterns of regulation indicates that rather than being a sudden switch, oocyte maturation in Drosophila is a progressive process, whereby mRNAs are translationally activated or repressed at different times throughout this developmental transition.

Another surprise was the identification of a set of mRNAs for which tail-length changes did not correspond to TE changes during oocyte maturation. This exception to the general pattern occurred for the mRNAs that had undergone deadenylation between oocyte stages 13 and 14 yet continued to be translated with relatively high efficiency (Figure 2—figure supplement 2). To escape the general regulatory environment of the cytoplasm, these mRNAs might exploit unique interactions with the translational machinery analogous to the translational activation of histone mRNAs through stem-loop binding protein (Cakmakci et al., 2008), or they might localize to a subcellular compartment that lacks coupling. The deadenylation of these mRNAs during oogenesis might prime them for rapid degradation during embryogenesis. Most mRNAs from genes encoding proteasome subunits fell into this class. Previous comparisons of the proteome and translation changes suggest that extensive proteolysis occurs at egg activation (Kronja et al., 2014b). Upregulation of the proteasome in late oogenesis might necessitate a mechanism to downregulate it rapidly during embryogenesis, perhaps facilitated by pre-deadenylating the corresponding mRNAs before egg activation.

The molecular mechanism that couples TE with poly(A)-tail length is unknown, as is the mechanism of the uncoupling that occurs at gastrulation. Nevertheless, our results, which show that widespread changes in poly(A)-tail length broadly reshape translational activity during oocyte and embryo development, demonstrate the importance of this coupling mechanism and provide a resource that documents the thousands of affected genes with information on the timing, magnitude, and inferred consequences of the tail-length changes for mRNAs from each of these genes. Moreover, the identification of unanticipated complexities and exceptions reveals the rich posttranscriptional regulatory landscape of oocytes and early embryos and points to additional mechanisms that operate for some mRNAs in specific settings, which can now be targeted for investigation.

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Author details

1. Stephen W Eichhorn

   1. Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, United States
   2. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States

   Contribution

   SWE, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-6410-4699

2. Alexander O Subtelny

   1. Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, United States
   2. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
   3. Harvard-MIT Division of Health Sciences and Technology, Cambridge, United States

   Contribution

   AOS, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Iva Kronja

   1. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
   2. Whitehead Institute for Biomedical Research, Cambridge, United States

   Contribution

   IK, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Jamie C Kwasnieski

   1. Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, United States
   2. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States

   Contribution

   JCK, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Terry L Orr-Weaver

   1. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
   2. Whitehead Institute for Biomedical Research, Cambridge, United States

   Contribution

   TLO-W, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   weaver@wi.mit.edu

   Competing interests

   The authors declare that no competing interests exist.

6. David P Bartel

   1. Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, United States
   2. Department of Biology, Massachusetts Institute of Technology, Cambridge, United States

   Contribution

   DPB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   dbartel@wi.mit.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-3872-2856

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