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Cytoplasmic polyadenylation and translational control
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Cytoplasmic polyadenylation and translational control Ana Villalba, Olga Coll and Fa´tima Gebauer Cytoplasmic polyadenylation is the process by which dormant, translationally inactive mRNAs become activated via the elongation of their poly(A) tails in the cytoplasm. This process is regulated by the conserved cytoplasmic polyadenylation element binding (CPEB) protein family. Recent studies have advanced our understanding of the molecular code that dictates the timing of CPEB-mediated poly(A) tail elongation and the extent of translational activation. In addition, evidence for CPEB-independent mechanisms has accumulated, and the breath of biological circumstances in which cytoplasmic polyadenylation plays a role has expanded. These observations underscore the versatility of CPEB as a translational regulator, and highlight the diversity of cytoplasmic polyadenylation mechanisms. Address Gene Regulation Programme, Centre for Genomic Regulation (CRG) and UPF, Dr Aiguader 88, 08003-Barcelona, Spain Corresponding author: Gebauer, Fa´tima ([email protected])
Current Opinion in Genetics & Development 2011, 21:452–457 This review comes from a themed issue on Differentiation and gene regulation Edited by Jessica Treisman and Joel Richter Available online 30th April 2011 0959-437X/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2011.04.006
Introduction Cytoplasmic polyadenylation was discovered nearly 40 years ago. Since then, much effort has been dedicated to decipher the molecular mechanism of this process, which is now known to play important roles in oocyte maturation, mitotic cell cycle progression, cellular senescence and synaptic plasticity. Most of the biochemistry of cytoplasmic polyadenylation has been elucidated in Xenopus oocytes induced to undergo meiotic maturation by stimulation with progesterone. During maturation, quiescent, prophase I (PI)-arrested oocytes (stage VI) progress to metaphase II (MII) concomitant with the cytoplasmic polyadenylation of transcripts encoding key cell cycle regulators [1,2]. Classical studies in this system identified two cis-acting sequences in the 30 UTR of substrate mRNAs: the conserved polyadenylation hexanucleotide (Hex), mainly consisting of AAUAAA or AUUAAA and also required for nuclear polyadenylation, and the less conserved cytoplasmic Current Opinion in Genetics & Development 2011, 21:452–457
polyadenylation element (CPE), with the general structure UUUUUA1–3U. Current models for cytoplasmic polyadenylation are centered on the CPE-binding (CPEB) protein, a family of factors whose founding member CPEB1 is essential for maturation [3]. A molecular code for CPEB-mediated regulation as well as CPEB-independent mechanisms have recently been proposed to establish the timing and extent of translational activation. In addition, studies in other systems suggest the potential for alternative CPE-independent and Hex-independent mechanisms, and have also expanded the range of biological situations under CPEB-mediated control. In this review, we highlight these advances starting by discussing current molecular mechanisms of cytoplasmic polyadenylation.
The mechanism of cytoplasmic polyadenylation A long (80–250 residues) poly(A) tail is thought to stimulate translation via the binding of poly(A)-binding protein (PABP), which establishes connections with the capbinding complex promoting the formation of a cap-to-tail closed-loop that confers translational efficiency to the mRNA (Figure 1). The cap-binding complex consists of the translation initiation factors eIF4E, eIF4G, and eIF4A. In particular, PABP binds to eIF4G, and this contact increases the affinity of eIF4E for the cap structure. mRNA-bound eIF4G recruits the 43S ribosomal complex via contacts with eIF3. Many translational control mechanisms modulate these early steps of translation initiation, and cytoplasmic polyadenylation is not an exception [4,5]. The best characterized mechanism of cytoplasmic polyadenylation is that occurring during Xenopus oocyte maturation. Polyadenylation in this system is activated concomitant with the phosphorylation of CPEB1 by Aurora A. CPEB1 behaves as a dual factor: it represses translation in its unphosphorylated state and activates translation of the same substrates upon phosphorylation. In addition to phosphorylated CPEB, the complex that drives polyadenylation contains a cytoplasmic form of the multisubunit factor CPSF (cleavage and polyadenylation specificity factor) bound to the Hex, the scaffolding protein Symplekin and the cytoplasmic poly(A) polymerase Gld-2 [6] (Figure 1, right panel). While there is general agreement in the composition of this complex, a number of possibilities have been proposed for the composition of the complex that mediates CPE-dependent repression in immature oocytes, leading to different models of CPE-mediated regulation. These models are discussed below. www.sciencedirect.com
Cytoplasmic polyadenylation Villalba, Coll and Gebauer 453
Figure 1
Activated mRNA
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Models for CPE-mediated repression and cytoplasmic polyadenylation. The CPE and the Hex are indicated as a square and hexagon, respectively. Proteins are shown with their names except for Symplekin, which is represented as a grey oval behind CPEB and CPSF. Several models for CPEBmediated repression in immature Xenopus oocytes are depicted. Upon progesterone stimulation, CPEB is phosphorylated (red star) and polyadenylation is activated. The poly(A) tail recruits PABP, which establishes connections with the cap-binding complex for translation initiation.
CPE-containing mRNAs are polyadenylated in the nucleus and subsequently loose their poly(A) tails by the action of poly(A)-ribonuclease (PARN) [7]. Deadenylation by PARN in the cytoplasm has been proposed as a key silencing mechanism in PI-arrested oocytes. PARN binds to unphosphorylated CPEB, and is found in complexes that also contain CPSF, GLD-2 and symplekin. The competition between the activities of Gld-2 and PARN in these complexes — the latter supposedly stronger — maintains a short length of the poly(A) tail in immature oocytes [7]. Upon progesterone stimulation, phosphorylation of CPEB expels PARN from the complex, allowing productive polyadenylation by Gld-2 and translational stimulation (Figure 1, Model 1). In earlier studies, the Richter lab found that CPEB phosphorylation increases its interaction with CPSF, resulting in strong polyadenylation [6,8]. This is consistent with a second model whereby the amount of polyadenylation-competent complexes increases upon maturation by a regulated switch operated by CPEB: immature oocytes would contain a repressor complex lacking CPSF, while maturing oocytes would contain a www.sciencedirect.com
complex composed of phosphorylated CPEB, GLD-2, and CPSF (Figure 1, Model 2). The repressor complex could contain PARN or other inhibitory molecules. For example, the CPEB-binding protein Maskin binds to eIF4E and blocks the formation of the cap-binding complex on the mRNA [9] (Model 2). Whether the Maskin and PARN mechanisms can occur on the same mRNA molecule is unclear, as PARN also binds to the cap structure and this binding is required to stimulate its activity [10]. In a different study, Minshall et al. found no evidence for CPEB binding to Maskin or PARN in mixed stage oocyte lysates [11]. Instead, these authors found direct interactions between CPEB, 4E-transporter (4E-T) and an isoform of eIF4E (eIF4E1b) that shows poor intrinsic binding for the cap structure and eIF4G. Thus, similar to other regulators [12], CPEB may repress translation by recruiting decoy isoforms of eIF4E (Figure 1, Model 3). This CPEB complex likely represents an early assembly present in growing oocytes, raising the possibility that CPEB represses translation by different mechanisms in distinct developmental stages. Current Opinion in Genetics & Development 2011, 21:452–457
454 Differentiation and gene regulation
These models are not necessarily mutually exclusive, specially if the complexes assemble in a sequencespecific manner on different mRNAs, or at different developmental times (see [13]).
wave of polyadenylation ensues that is required for MI– MII transition. A third wave of polyadenylation (late–late) occurs in interkinesis to allow mature oocytes to arrest in MII awaiting fertilization [2].
mRNAs generally contain multiple regulatory signals that must be integrated to yield a correct translational output. One of these is the Pumilio-binding element (PBE), which is often found in association with the CPE. Pumilio binding to the PBE fine-tunes CPE-mediated regulation [14]. PUF (Pumilio and FBF) family proteins act by repressing mRNA translation via recruitment of the deadenylase complex CCR4-POP2-NOT, but they can also stimulate translation via recruitment of GLD-2 [15]. In terms of CPE-mediated translation, Pum seems to preserve this dual role, as it may promote translational repression by interacting with CPEB and also activation by stabilizing CPEB on nonconsensus CPEs [16,17].
Pique´ et al. [17] have recently proposed a model whereby the number of CPEs, their relative position with respect to the Hex, and the presence of additional modulatory elements explain these waves of polyadenylation (summarized in Figure 2). This combinatorial code has a strong predictive power, as the behavior of about 90% of randomly selected mRNAs could be predicted [17]. An alternative model, however, proposes that early versus late polyadenylation depend on distinct regulatory elements: early polyadenylation is driven by Msi binding to the PRE and is independent of the CPE, while late polyadenylation is executed by CPEB [18–20,27] (Figure 2). Whether Msi can recruit the polyadenylation complex remains to be determined. As many mRNAs contain several cis-acting elements in addition to CPEs and PREs, a future challenge will be to determine how the output of these signals is integrated to generate a specific polyadenylation pattern.
A different cis-acting sequence is the polyadenylation response element (PRE) recognized by Musashi (Msi), a protein essential for oocyte maturation [18,19]. The PRE mediates polyadenylation in a CPE-independent but Hex-dependent manner, suggesting that a complex lacking CPEB may mediate cytoplasmic polyadenylation [18,20]. Recent evidence indeed points to the existence of alternative machineries. Using functional competition assays, it has been found that polyadenylation of Toll mRNA during early Drosophila embryogenesis is directed by a complex that is insensitive to titration with CPE-containing and Hex-containing transcripts, suggesting that a noncanonical machinery operates for polyadenylation of Toll [21]. Work in Caenorhabditis elegans indicates that GLD-2 can be recruited to the mRNA by multiple RNA-binding factors [22,23,24], and that additional cytoplasmic poly(A) polymerases exist that are recruited to transcripts via RBP adaptors [25]. In addition, nuclear poly(A) polymerases can also function in cytoplasmic polyadenylation [26]. It is likely that the capacity of RBPs to recruit diverse poly(A) polymerases in a sequence-specific manner will be at the basis of the diversity of foreseeable cytoplasmic polyadenylation mechanisms.
The CPEB family contains four members whose activities might also influence the pattern of translational regulation [3]. These proteins are most similar in their C-terminal RNA-binding domains, while they show significant divergence in their regulatory N-terminal domains, suggesting that they could recognize overlapping sets of transcripts for distinct regulatory purposes. CPEB1 drives polyadenylation during oocyte maturation but, as mentioned above, is heavily degraded after MI. Igea and Me´ndez [28] found that CPEB4 replaces CPEB1 in interkinesis through a translational loop that involves polyadenylation and activation of CPEB4 mRNA by CPEB1 at earlier time points. CPEB1 also induces the translation of C3H-4, an AU-rich (ARE)-binding protein which recruits deadenylases that oppose CPEB activity [29] (Figure 2). Thus, CPEB1 establishes positive and negative feed-back loops that drive forward meiotic progression.
Additional examples of biological relevance The cytoplasmic polyadenylation code In stage VI oocytes, not all CPE-containing mRNAs are masked. Similarly, during oocyte maturation transcripts are not activated simultaneously, but rather show distinct timings and extents of polyadenylation and activation. Progesterone first induces an early wave of cytoplasmic polyadenylation that is coincident with phosphorylation of CPEB by Aurora A. One of the substrates in this early wave encodes Mos, a kinase that triggers a signaling cascade that results in activation of MPF (a complex of cdc2 and cyclin B) and progression to Metaphase I (MI) (Figure 2). At or around MI, cdc2 phosphorylates CPEB at many sites and targets it for destruction. Concomitantly, a second (late) Current Opinion in Genetics & Development 2011, 21:452–457
In addition to oocyte maturation, CPEB-dependent translation contributes to the synaptic changes that underlie learning and memory, a process referred to as synaptic plasticity [30,31]. A role of CPEB in long term memory is supported by findings in Drosophila showing that the CPEB2-4 homolog Orb2 is essential for this process [32]. Although a polyadenylation/translation function for Orb2 has not been tested, polyadenylation by Gld-2 is certainly involved [33]. Mammalian CPEB regulates the polyadenylation and translation of alpha-CaMKII mRNA in synaptic terminals upon stimulation [34,35] and facilitates transport of mRNAs to dendrites [36]. Intriguingly, Aplysia CPEB (ApCPEB) contains a Q-rich www.sciencedirect.com
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Figure 2
Progesterone (1) Maturation:
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Current Opinion in Genetics & Development
Timing of cytoplasmic polyadenylation during oocyte maturation. The different stages of the maturation process are indicated in the first row (P, prophase; GVBD, germinal vesicle breakdown; M, metaphase). In immature, PI-arrested oocytes, mRNAs are translationally repressed, and become activated upon progesterone stimulation through three waves of polyadenylation: early, late and late–late (second row). These waves are concomitant with phosphorylation of CPEB1, first by Aurora A (big star) and then by cdc2 (small stars), the latter resulting in degradation of the protein and its substitution by CPEB4 in subsequent maturation stages. Two models have been proposed to explain the timing of polyadenylation: the CPEcombinatorial code and the Msi model. The optimal configuration of cis-acting elements in the CPE-code is depicted, together with their binding factors. (1) Translational repression requires a dimer of CPEB. (2) Early polyadenylation requires a CPE at an optimal distance from the Hex. (3) Late polyadenylation occurs on mRNAs with two CPEs, one of them overlapping the Hex; polyadenylation of these transcripts requires that CPEB is partially degraded, which results in stochastic removal of CPEB from the overlapping Hex and productive polyadenylation. (4) Deadenylation activities delay polyadenylation throughout maturation. Late–late polyadenylation occurs on transcripts with optimal ‘late’ configurations that also contain AUrich elements (ARE). The Msi model (last row) proposes that early polyadenylation is independent of CPEB and is driven by Msi binding to the PRE/ MBE (Musashi binding element), while late polyadenylation is CPEB-dependent.
amino-terminal domain that seems to confer prion-like properties to the protein, such as the capacity to form selfperpetuating multimers [37,38]. Surprisingly, and contrary to other prion proteins, the presence of these multimers correlates with the active state of the protein [38]. These multimers have been proposed to contribute to maintain the long lasting changes that accompany LTF [39]. An important remaining question is to establish how an amyloid CPEB aggregate can sustain the necessary interactions for translation stimulation. Cytoplasmic polyadenylation also contributes to early embryonic divisions, which are characterized by rapid cycles of DNA synthesis and mitosis without intervening phases [40,41]. A recent report shows that CPEB1 and www.sciencedirect.com
CPEB4 are important for somatic cell divisions as well, and that they can regulate the poly(A) tail elongation of many mRNAs [42]. It will be interesting to determine whether localized CPEB-driven translation at spindles plays a role in mitosis, as has been shown to be the case in meiosis [43]. In addition, CPEB1 is required for senescence of human diploid fibroblasts and controls bioenergetics in part by regulating the translation of p53 mRNA [44]. Functions of cytoplasmic polyadenylation factors in other aspects of gene expression are also promising. For example, CPEB is present in the nucleus, where it associates with the nuclear polyadenylation machinery [45]. Although nuclear functions for CPEB have not been reported, future investigations are likely to expand the activities of this important regulator. Current Opinion in Genetics & Development 2011, 21:452–457
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Conclusions Translational control by cytoplasmic polyadenylation is a mechanism that regulates a diverse array of biological phenomena. Studies on the classical CPE-mediated mechanism have documented a variety of CPEB-containing complexes. Further evidence suggests the existence of alternative assemblies that mediate polyadenylation in a noncanonical fashion. The versatility of RNA-binding factors to recruit effectors (e.g. poly(A) polymerases) in a sequence-specific fashion, together with the fact that mRNAs usually contain multiple regulatory elements, provides an enormous combinatorial potential for cytoplasmic polyadenylation and translational control. Signaling to polyadenylation-mediated translation is a field in its infancy, with detailed knowledge limited to oocyte maturation. Understanding the building blocks of translational control, their combinatorial code and the signaling pathways by which they are regulated are challenges for the future that will provide important insights into relevant aspects of Biology, from cell cycle regulation to synaptic plasticity.
Acknowledgements We thank Juan Valca´rcel and Rau´l Me´ndez for carefully reading this manuscript. We apologize to those authors whose work could not be mentioned due to space limitations. A.V. is supported by an FPI fellowship from the Spanish Ministry of Science and Innovation. Work in F. Gebauer lab is supported by grants BFU2009-08243 and Consolider CSD2009-00080 from the Spanish Ministry of Science and Innovation.
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Current Opinion in Genetics & Development 2011, 21:452–457
Cytoplasmic polyadenylation and translational control Ana Villalba, Olga Coll and Fa´tima Gebauer Cytoplasmic polyadenylation is the process by which dormant, translationally inactive mRNAs become activated via the elongation of their poly(A) tails in the cytoplasm. This process is regulated by the conserved cytoplasmic polyadenylation element binding (CPEB) protein family. Recent studies have advanced our understanding of the molecular code that dictates the timing of CPEB-mediated poly(A) tail elongation and the extent of translational activation. In addition, evidence for CPEB-independent mechanisms has accumulated, and the breath of biological circumstances in which cytoplasmic polyadenylation plays a role has expanded. These observations underscore the versatility of CPEB as a translational regulator, and highlight the diversity of cytoplasmic polyadenylation mechanisms. Address Gene Regulation Programme, Centre for Genomic Regulation (CRG) and UPF, Dr Aiguader 88, 08003-Barcelona, Spain Corresponding author: Gebauer, Fa´tima ([email protected])
Current Opinion in Genetics & Development 2011, 21:452–457 This review comes from a themed issue on Differentiation and gene regulation Edited by Jessica Treisman and Joel Richter Available online 30th April 2011 0959-437X/$ – see front matter # 2011 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2011.04.006
Introduction Cytoplasmic polyadenylation was discovered nearly 40 years ago. Since then, much effort has been dedicated to decipher the molecular mechanism of this process, which is now known to play important roles in oocyte maturation, mitotic cell cycle progression, cellular senescence and synaptic plasticity. Most of the biochemistry of cytoplasmic polyadenylation has been elucidated in Xenopus oocytes induced to undergo meiotic maturation by stimulation with progesterone. During maturation, quiescent, prophase I (PI)-arrested oocytes (stage VI) progress to metaphase II (MII) concomitant with the cytoplasmic polyadenylation of transcripts encoding key cell cycle regulators [1,2]. Classical studies in this system identified two cis-acting sequences in the 30 UTR of substrate mRNAs: the conserved polyadenylation hexanucleotide (Hex), mainly consisting of AAUAAA or AUUAAA and also required for nuclear polyadenylation, and the less conserved cytoplasmic Current Opinion in Genetics & Development 2011, 21:452–457
polyadenylation element (CPE), with the general structure UUUUUA1–3U. Current models for cytoplasmic polyadenylation are centered on the CPE-binding (CPEB) protein, a family of factors whose founding member CPEB1 is essential for maturation [3]. A molecular code for CPEB-mediated regulation as well as CPEB-independent mechanisms have recently been proposed to establish the timing and extent of translational activation. In addition, studies in other systems suggest the potential for alternative CPE-independent and Hex-independent mechanisms, and have also expanded the range of biological situations under CPEB-mediated control. In this review, we highlight these advances starting by discussing current molecular mechanisms of cytoplasmic polyadenylation.
The mechanism of cytoplasmic polyadenylation A long (80–250 residues) poly(A) tail is thought to stimulate translation via the binding of poly(A)-binding protein (PABP), which establishes connections with the capbinding complex promoting the formation of a cap-to-tail closed-loop that confers translational efficiency to the mRNA (Figure 1). The cap-binding complex consists of the translation initiation factors eIF4E, eIF4G, and eIF4A. In particular, PABP binds to eIF4G, and this contact increases the affinity of eIF4E for the cap structure. mRNA-bound eIF4G recruits the 43S ribosomal complex via contacts with eIF3. Many translational control mechanisms modulate these early steps of translation initiation, and cytoplasmic polyadenylation is not an exception [4,5]. The best characterized mechanism of cytoplasmic polyadenylation is that occurring during Xenopus oocyte maturation. Polyadenylation in this system is activated concomitant with the phosphorylation of CPEB1 by Aurora A. CPEB1 behaves as a dual factor: it represses translation in its unphosphorylated state and activates translation of the same substrates upon phosphorylation. In addition to phosphorylated CPEB, the complex that drives polyadenylation contains a cytoplasmic form of the multisubunit factor CPSF (cleavage and polyadenylation specificity factor) bound to the Hex, the scaffolding protein Symplekin and the cytoplasmic poly(A) polymerase Gld-2 [6] (Figure 1, right panel). While there is general agreement in the composition of this complex, a number of possibilities have been proposed for the composition of the complex that mediates CPE-dependent repression in immature oocytes, leading to different models of CPE-mediated regulation. These models are discussed below. www.sciencedirect.com
Cytoplasmic polyadenylation Villalba, Coll and Gebauer 453
Figure 1
Activated mRNA
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4E-T CPEB AA Current Opinion in Genetics & Development
Models for CPE-mediated repression and cytoplasmic polyadenylation. The CPE and the Hex are indicated as a square and hexagon, respectively. Proteins are shown with their names except for Symplekin, which is represented as a grey oval behind CPEB and CPSF. Several models for CPEBmediated repression in immature Xenopus oocytes are depicted. Upon progesterone stimulation, CPEB is phosphorylated (red star) and polyadenylation is activated. The poly(A) tail recruits PABP, which establishes connections with the cap-binding complex for translation initiation.
CPE-containing mRNAs are polyadenylated in the nucleus and subsequently loose their poly(A) tails by the action of poly(A)-ribonuclease (PARN) [7]. Deadenylation by PARN in the cytoplasm has been proposed as a key silencing mechanism in PI-arrested oocytes. PARN binds to unphosphorylated CPEB, and is found in complexes that also contain CPSF, GLD-2 and symplekin. The competition between the activities of Gld-2 and PARN in these complexes — the latter supposedly stronger — maintains a short length of the poly(A) tail in immature oocytes [7]. Upon progesterone stimulation, phosphorylation of CPEB expels PARN from the complex, allowing productive polyadenylation by Gld-2 and translational stimulation (Figure 1, Model 1). In earlier studies, the Richter lab found that CPEB phosphorylation increases its interaction with CPSF, resulting in strong polyadenylation [6,8]. This is consistent with a second model whereby the amount of polyadenylation-competent complexes increases upon maturation by a regulated switch operated by CPEB: immature oocytes would contain a repressor complex lacking CPSF, while maturing oocytes would contain a www.sciencedirect.com
complex composed of phosphorylated CPEB, GLD-2, and CPSF (Figure 1, Model 2). The repressor complex could contain PARN or other inhibitory molecules. For example, the CPEB-binding protein Maskin binds to eIF4E and blocks the formation of the cap-binding complex on the mRNA [9] (Model 2). Whether the Maskin and PARN mechanisms can occur on the same mRNA molecule is unclear, as PARN also binds to the cap structure and this binding is required to stimulate its activity [10]. In a different study, Minshall et al. found no evidence for CPEB binding to Maskin or PARN in mixed stage oocyte lysates [11]. Instead, these authors found direct interactions between CPEB, 4E-transporter (4E-T) and an isoform of eIF4E (eIF4E1b) that shows poor intrinsic binding for the cap structure and eIF4G. Thus, similar to other regulators [12], CPEB may repress translation by recruiting decoy isoforms of eIF4E (Figure 1, Model 3). This CPEB complex likely represents an early assembly present in growing oocytes, raising the possibility that CPEB represses translation by different mechanisms in distinct developmental stages. Current Opinion in Genetics & Development 2011, 21:452–457
454 Differentiation and gene regulation
These models are not necessarily mutually exclusive, specially if the complexes assemble in a sequencespecific manner on different mRNAs, or at different developmental times (see [13]).
wave of polyadenylation ensues that is required for MI– MII transition. A third wave of polyadenylation (late–late) occurs in interkinesis to allow mature oocytes to arrest in MII awaiting fertilization [2].
mRNAs generally contain multiple regulatory signals that must be integrated to yield a correct translational output. One of these is the Pumilio-binding element (PBE), which is often found in association with the CPE. Pumilio binding to the PBE fine-tunes CPE-mediated regulation [14]. PUF (Pumilio and FBF) family proteins act by repressing mRNA translation via recruitment of the deadenylase complex CCR4-POP2-NOT, but they can also stimulate translation via recruitment of GLD-2 [15]. In terms of CPE-mediated translation, Pum seems to preserve this dual role, as it may promote translational repression by interacting with CPEB and also activation by stabilizing CPEB on nonconsensus CPEs [16,17].
Pique´ et al. [17] have recently proposed a model whereby the number of CPEs, their relative position with respect to the Hex, and the presence of additional modulatory elements explain these waves of polyadenylation (summarized in Figure 2). This combinatorial code has a strong predictive power, as the behavior of about 90% of randomly selected mRNAs could be predicted [17]. An alternative model, however, proposes that early versus late polyadenylation depend on distinct regulatory elements: early polyadenylation is driven by Msi binding to the PRE and is independent of the CPE, while late polyadenylation is executed by CPEB [18–20,27] (Figure 2). Whether Msi can recruit the polyadenylation complex remains to be determined. As many mRNAs contain several cis-acting elements in addition to CPEs and PREs, a future challenge will be to determine how the output of these signals is integrated to generate a specific polyadenylation pattern.
A different cis-acting sequence is the polyadenylation response element (PRE) recognized by Musashi (Msi), a protein essential for oocyte maturation [18,19]. The PRE mediates polyadenylation in a CPE-independent but Hex-dependent manner, suggesting that a complex lacking CPEB may mediate cytoplasmic polyadenylation [18,20]. Recent evidence indeed points to the existence of alternative machineries. Using functional competition assays, it has been found that polyadenylation of Toll mRNA during early Drosophila embryogenesis is directed by a complex that is insensitive to titration with CPE-containing and Hex-containing transcripts, suggesting that a noncanonical machinery operates for polyadenylation of Toll [21]. Work in Caenorhabditis elegans indicates that GLD-2 can be recruited to the mRNA by multiple RNA-binding factors [22,23,24], and that additional cytoplasmic poly(A) polymerases exist that are recruited to transcripts via RBP adaptors [25]. In addition, nuclear poly(A) polymerases can also function in cytoplasmic polyadenylation [26]. It is likely that the capacity of RBPs to recruit diverse poly(A) polymerases in a sequence-specific manner will be at the basis of the diversity of foreseeable cytoplasmic polyadenylation mechanisms.
The CPEB family contains four members whose activities might also influence the pattern of translational regulation [3]. These proteins are most similar in their C-terminal RNA-binding domains, while they show significant divergence in their regulatory N-terminal domains, suggesting that they could recognize overlapping sets of transcripts for distinct regulatory purposes. CPEB1 drives polyadenylation during oocyte maturation but, as mentioned above, is heavily degraded after MI. Igea and Me´ndez [28] found that CPEB4 replaces CPEB1 in interkinesis through a translational loop that involves polyadenylation and activation of CPEB4 mRNA by CPEB1 at earlier time points. CPEB1 also induces the translation of C3H-4, an AU-rich (ARE)-binding protein which recruits deadenylases that oppose CPEB activity [29] (Figure 2). Thus, CPEB1 establishes positive and negative feed-back loops that drive forward meiotic progression.
Additional examples of biological relevance The cytoplasmic polyadenylation code In stage VI oocytes, not all CPE-containing mRNAs are masked. Similarly, during oocyte maturation transcripts are not activated simultaneously, but rather show distinct timings and extents of polyadenylation and activation. Progesterone first induces an early wave of cytoplasmic polyadenylation that is coincident with phosphorylation of CPEB by Aurora A. One of the substrates in this early wave encodes Mos, a kinase that triggers a signaling cascade that results in activation of MPF (a complex of cdc2 and cyclin B) and progression to Metaphase I (MI) (Figure 2). At or around MI, cdc2 phosphorylates CPEB at many sites and targets it for destruction. Concomitantly, a second (late) Current Opinion in Genetics & Development 2011, 21:452–457
In addition to oocyte maturation, CPEB-dependent translation contributes to the synaptic changes that underlie learning and memory, a process referred to as synaptic plasticity [30,31]. A role of CPEB in long term memory is supported by findings in Drosophila showing that the CPEB2-4 homolog Orb2 is essential for this process [32]. Although a polyadenylation/translation function for Orb2 has not been tested, polyadenylation by Gld-2 is certainly involved [33]. Mammalian CPEB regulates the polyadenylation and translation of alpha-CaMKII mRNA in synaptic terminals upon stimulation [34,35] and facilitates transport of mRNAs to dendrites [36]. Intriguingly, Aplysia CPEB (ApCPEB) contains a Q-rich www.sciencedirect.com
Cytoplasmic polyadenylation Villalba, Coll and Gebauer 455
Figure 2
Progesterone (1) Maturation:
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Current Opinion in Genetics & Development
Timing of cytoplasmic polyadenylation during oocyte maturation. The different stages of the maturation process are indicated in the first row (P, prophase; GVBD, germinal vesicle breakdown; M, metaphase). In immature, PI-arrested oocytes, mRNAs are translationally repressed, and become activated upon progesterone stimulation through three waves of polyadenylation: early, late and late–late (second row). These waves are concomitant with phosphorylation of CPEB1, first by Aurora A (big star) and then by cdc2 (small stars), the latter resulting in degradation of the protein and its substitution by CPEB4 in subsequent maturation stages. Two models have been proposed to explain the timing of polyadenylation: the CPEcombinatorial code and the Msi model. The optimal configuration of cis-acting elements in the CPE-code is depicted, together with their binding factors. (1) Translational repression requires a dimer of CPEB. (2) Early polyadenylation requires a CPE at an optimal distance from the Hex. (3) Late polyadenylation occurs on mRNAs with two CPEs, one of them overlapping the Hex; polyadenylation of these transcripts requires that CPEB is partially degraded, which results in stochastic removal of CPEB from the overlapping Hex and productive polyadenylation. (4) Deadenylation activities delay polyadenylation throughout maturation. Late–late polyadenylation occurs on transcripts with optimal ‘late’ configurations that also contain AUrich elements (ARE). The Msi model (last row) proposes that early polyadenylation is independent of CPEB and is driven by Msi binding to the PRE/ MBE (Musashi binding element), while late polyadenylation is CPEB-dependent.
amino-terminal domain that seems to confer prion-like properties to the protein, such as the capacity to form selfperpetuating multimers [37,38]. Surprisingly, and contrary to other prion proteins, the presence of these multimers correlates with the active state of the protein [38]. These multimers have been proposed to contribute to maintain the long lasting changes that accompany LTF [39]. An important remaining question is to establish how an amyloid CPEB aggregate can sustain the necessary interactions for translation stimulation. Cytoplasmic polyadenylation also contributes to early embryonic divisions, which are characterized by rapid cycles of DNA synthesis and mitosis without intervening phases [40,41]. A recent report shows that CPEB1 and www.sciencedirect.com
CPEB4 are important for somatic cell divisions as well, and that they can regulate the poly(A) tail elongation of many mRNAs [42]. It will be interesting to determine whether localized CPEB-driven translation at spindles plays a role in mitosis, as has been shown to be the case in meiosis [43]. In addition, CPEB1 is required for senescence of human diploid fibroblasts and controls bioenergetics in part by regulating the translation of p53 mRNA [44]. Functions of cytoplasmic polyadenylation factors in other aspects of gene expression are also promising. For example, CPEB is present in the nucleus, where it associates with the nuclear polyadenylation machinery [45]. Although nuclear functions for CPEB have not been reported, future investigations are likely to expand the activities of this important regulator. Current Opinion in Genetics & Development 2011, 21:452–457
456 Differentiation and gene regulation
Conclusions Translational control by cytoplasmic polyadenylation is a mechanism that regulates a diverse array of biological phenomena. Studies on the classical CPE-mediated mechanism have documented a variety of CPEB-containing complexes. Further evidence suggests the existence of alternative assemblies that mediate polyadenylation in a noncanonical fashion. The versatility of RNA-binding factors to recruit effectors (e.g. poly(A) polymerases) in a sequence-specific fashion, together with the fact that mRNAs usually contain multiple regulatory elements, provides an enormous combinatorial potential for cytoplasmic polyadenylation and translational control. Signaling to polyadenylation-mediated translation is a field in its infancy, with detailed knowledge limited to oocyte maturation. Understanding the building blocks of translational control, their combinatorial code and the signaling pathways by which they are regulated are challenges for the future that will provide important insights into relevant aspects of Biology, from cell cycle regulation to synaptic plasticity.
Acknowledgements We thank Juan Valca´rcel and Rau´l Me´ndez for carefully reading this manuscript. We apologize to those authors whose work could not be mentioned due to space limitations. A.V. is supported by an FPI fellowship from the Spanish Ministry of Science and Innovation. Work in F. Gebauer lab is supported by grants BFU2009-08243 and Consolider CSD2009-00080 from the Spanish Ministry of Science and Innovation.
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