REPRODUCTIONREVIEW
The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes
Matthew Brook1,2,3, Joel W S Smith2 and Nicola K Gray1,2,3 1MRC Human Reproductive Sciences Unit, Queen’s Medical Research Institute, Centre for Reproductive Biology, 47 Little France Crescent, Edinburgh EH16 4TJ, UK, 2MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK and 3School of Clinical Sciences and Community Health, University of Edinburgh, The Chancellor’s Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK Correspondence should be addressed to N K Gray; Email: [email protected]
JWS Smith is now at Edinburgh Research and Innovation Ltd, 1-7 Roxburgh Street, Edinburgh EH8 9TA, UK
Abstract
Gametogenesis is a highly complex process that requires the exquisite temporal, spatial and amplitudinal regulation of gene expression at multiple levels. Translational regulation is important in a wide variety of cell types but may be even more prevalent in germ cells, where periods of transcriptional quiescence necessitate the use of post-transcriptional mechanisms to effect changes in gene expression. Consistent with this, studies in multiple animal models have revealed an essential role for mRNA translation in the establishment and maintenance of reproductive competence. While studies in humans are less advanced, emerging evidence suggests that translational regulation plays a similarly important role in human germ cells and fertility. This review highlights specific mechanisms of translational regulation that play critical roles in oogenesis by activating subsets of mRNAs. These mRNAs are activated in a strictly determined temporal manner via elements located within their 30UTR, which serve as binding sites for trans-acting factors. While we concentrate on oogenesis, these regulatory events also play important roles during spermatogenesis. In particular, we focus on the deleted in azoospermia-like (DAZL) family of proteins, recently implicated in the translational control of specific mRNAs in germ cells; their relationship with the general translation initiation factor poly(A)-binding protein (PABP) and the process of cytoplasmic mRNA polyadenylation. Reproduction (2009) 137 595–617
Introduction translational control processes are evolutionarily con- w served, albeit to varying extents. We primarily discuss Impaired fertility affects 15% of couples worldwide studies of 30UTR-mediated translational activation with a significant proportion of cases being due to during oogenesis in small laboratory vertebrates such defective gametogenesis (Matzuk & Lamb 2008). In as Xenopus laevis and mouse. order to define possible points of therapeutic interven- X. laevis has proved an extremely powerful tool for tion in infertility, it is necessary to have an in-depth dissecting the molecular mechanisms and signalling understanding of the normal processes of gametogenesis pathways that regulate gene expression during oogen- and, in particular, to delineate the molecular esis. Indeed many key control mechanisms that operate mechanisms by which gametogenesis is regulated. In in mammalian oogenesis were first described using recent years, a great deal of research has concentrated on X. laevis oocytes. One reason for the popularity of the the control of gene expression during gametogenesis X. laevis model is that the seasonality of X. laevis and, more specifically, has investigated the important ovulation can be uncoupled and hundreds of oocytes of role of translational control during oogenesis (Piccioni different, clearly identifiable, stages can be recovered et al. 2005; see Box 1 and Fig. 1 for an overview of from a single ovary. These oocytes can be readily oogenesis). The limited availability of human ovarian maintained and matured in vitro. Importantly, the large tissue and the tractability of organisms such as mice, size of these oocytes make them amenable to micro- Xenopus, sheep, cows, Drosophila and Caenorhabditis injection with exogenous DNAs/RNAs/proteins/drugs elegans means that most studies are performed using and subsequent biochemical assays. Most studies have these models, in which many of the key oogenic and focused on translational regulation during oocyte
q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-08-0524 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/26/2021 08:03:02PM via free access 596 M Brook and others
Box 1 A comparative overview of oogenesis (see also Fig. 1). Primordial germ cells (PGCs) originate in the early embryo distinct from the location of the developing gonad. In Xenopus laevis, PGCs derive from a cellular subset that inherited oocyte ‘germ-plasm’ during early embryonic asymmetric mitoses (Nieuwkoop & Faber 1994, Sive et al.1999). Germ-plasm describes a region of mitochondrial- rich ooplasm containing numerous mRNA-rich germinal granules. Human and mouse oocytes have no recognisable germ-plasm and PGCs do not appear to differentiate from a pre-determined cell population. Rather, mouse PGCs differentiate in response to extracellular signals derived from the proximal epiblast or primitive streak of the early embryo. PGCs of each species then proliferate and migrate to the developing gonad. PGC migration is completed prior to ovarian sexual differentiation but the germ cells continue to proliferate. In human and mouse ovaries the oogonia subsequently cease to proliferate and enter meiosis, whereas the X. laevis ovary retains a population of mixed primary oogonia (self-renewing) and nests of secondary oogonia (committed to oocyte differentiation; Nieuwkoop & Faber 1994, Sive et al.1999). The retention of self-renewing primary oogonia in X. laevis facilitates seasonal production of large numbers of oocytes, but is fundamentally different from mammalian oogenesis. The onset of meiosis I in oogonia occurs during embryogenesis in humans and mice and prior to metamorphosis in X. laevis. Human oogonia asynchronously begin to enter meiosis I in early second trimester and mice oogonia synchronously enter meiosis I at E13.5. A large proportion of human and mouse oogonia die during meiosis I in a process called atresia, with most cell death occurring during late-pachytene or dichtyate. The dichtyate arrest (prophase I) of surviving human oogonia is complete by late third trimester and persists for up to 45 years. X. laevis oogonia begin to enter meiosis I from stage 55 (wE32) onwardswith a marked increase in entry rate occurring at stage 56 (wE38). By stage 62 (wE50) most oogonia have entered diplotene of meiosis I, termed stage I oocytes. Several thousand X. laevis oocytes then progress through diplotene until many stage VI oocytes are present in the ovary (Nieuwkoop & Faber 1994, Sive et al.1999). During diplotene, oocytes synthesise huge amounts of rRNA, tRNAs, mitochondria, proteins and maternal mRNAs to prepare for their post-fertilization biosynthetic requirements until zygotic transcription resumes. This occurs after 1, 2–3 or 12 post-fertilization mitotic divisions in mouse, human and X. laevis respectively (Sive et al. 1999, Matova & Cooley 2001, Bownes & Pathirana 2003). Unlike mammals, X. laevis embryos do not receive nutrients placentally and instead oocytes accumulate a nutrient store during diplotene: a process termed vitellogenesis. Liver-secreted vitellogenin accumulates in oocytes until, by stage V, it comprises w80% of the ooplasm and accounts for the w4000-fold greater volume of a X. laevis oocyte compared with a mouse oocyte (Nieuwkoop & Faber 1994, Sive et al.1999). However, although transcription continues during diplotene only w2% of the ribosomes in late diplotene X. laevis oocytes are engaged in active translation and only w20% of the mRNAs are translated; indicating that the majority of the mRNA population is translationally silenced. Folliculogenesis and ovulation differ between mammals and X. laevis, although there are some significant similarities. In humans w20 primordial follicles/day become activated, in a poorly understood process, and then develop in a hormone/steroid-independent manner for w65 days. During this time the granulosa cells (GCs) proliferate, thecal cells derived from the stroma surround the growing follicle and the enclosed granulosa cells begin to differentiate. After this time GC proliferation becomes FSH-dependent, an antral space develops and the oocyte is surrounded by specialized cumulus granulosa cells (termed a Graafian follicle). Ultimately, only a single follicle is sufficiently developed to survive when FSH-levels decline mid-menstrually. It is for this reason that humans are usually mono-ovulatory.Mouse follicles can survive in lower FSH concentrations and, consequently,several follicles progress to ovulation. In mammals, a surge in circulating LH levels stimulates Graafian follicle oocytes to reinitiate meiosis. In X. laevis, the oocyte is surrounded by a single layer of follicle cells which secrete progesterone in response to circulating gonadotrophins and induce the oocyte to resume meiosis. The completion of meiosis I and progression through to metaphase of meiosis II is termed maturation and is highly conserved between mammals and X. laevis (see Box 2 and Fig. 2 for a more detailed overview of oocyte maturation; reviewed in (Schmitt & Nebreda 2002, Vasudevan et al. 2006)). Hence, X. laevis data have greatly informed studies of oocyte maturation in mammals. maturation (see Box 2 and Fig. 2 for an overview of can be easily scored by the appearance of a white spot oocyte maturation) since their transcriptional quiescence on the animal pole. means that changes in the pattern of protein synthesis Mouse models have greatly facilitated the study of can only be achieved via the activation, repression or mammalian oogenesis. While the multiovulatory nature destruction of pre-existing stored mRNAs. Many of the and lack of menstruation in mice differs from humans, key regulatory steps in maturation are conserved from the mouse ovary and the hormonal regulation of Xenopus to human and oocyte maturation in X. laevis oogenesis/folliculogenesis are comparable in many key
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Figure 1 Schematic to illustrate the comparative timing and duration of key events in vertebrate oogenesis. Timings are shown (where known) for the completion of the major primordial germ cell (PGC) pre-meiotic events (orange arrows). Due to the more asynchronous nature of the entry of the PGC/oogonia population into meiosis in human and X. laevis, the durations of individual stages of meiosis/folliculogenesis relate to the progress of an individual oocyte/follicle (yellow arrows). See Box 1 (or Matova & Cooley 2001) for a brief comparative review of vertebrate oogenesis. Xenopus germ-plasm can be detected throughout early embryogenesis, where it plays an important role in PGC specification, but the PGCs become embedded in the dorsal endoderm by stage 40 prior to migration to the site of genital ridge formation (Nieuwkoop & Faber 1994, Sive et al. 1999). A schematic of particular meiotic stages and pictorial representations of X. laevis oogenesis and mammalian folliculogenesis are also shown. GVBD, germinal vesicle breakdown. aspects. Their short oestrus and reproductive cycle is also DAZL family of translational activator proteins and their advantageous and the seasonality of reproduction is bred molecular and functional interactions with the PABP out of most laboratory strains. Additionally, the genetic family of translation initiation factors. manipulation of mice has proved extremely valuable to the study of both male and female gametogenesis; a technique that is not as widely applied in the tetraploid Translational regulation X. laevis. However, this advantage is countered by the Translational regulation is usually defined as a change in fact that it is difficult to obtain sufficient numbers of the rate of protein synthesis without a corresponding mouse oocytes to facilitate molecular and biochemical change in mRNA levels. However, this is an over- studies. simplification as translation and mRNA turnover are In this review, we will focus on the molecular often tightly coupled and alterations in translation can mechanisms of 30UTR mediated translational activation have downstream effects on mRNA stability (Newbury that play critical roles in oogenesis and highlight the 2006). Translation can also be spatially regulated to contributions of the X. laevis and mouse model systems establish protein gradients via localization of mRNAs to the understanding of these regulatory events. In and/or regulatory factors (Huang & Richter 2004). particular, we discuss the emerging importance of the Translational control therefore facilitates the generation www.reproduction-online.org Reproduction (2009) 137 595–617
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Box 2 An overview of the major signalling and gene expression events that regulate vertebrate oocyte maturation (see also Fig. 2). Maturation is triggered by progesterone in X. laevis, or LH in mammals, causing a rapid inhibition of adenylate cyclase activity (AC) and subsequent decline in cAMP levels, thereby reducing protein kinase A (PKA) activity and initiating a number of intracellular signalling cascades. The earliest regulatory events in maturation are poorly understood but, in X. laevis, rapid inducer of G2/M progression in oocytes (RINGO)/speedy (SPY) mRNA translation is initiated leading to activation of CDK2, aurora A and additional intracellular signalling pathways (the latter is not depicted) (Cheng et al. 2005, Padmanabhan & Richter 2006, Kim & Richter 2007). These events in turn lead to the translational upregulation of mRNAs encoding key meiotic proteins via modulation of their poly(A) tail length (including c-Mos, cyclin B1 and Wee1). One of the key events in vertebrate oocyte maturation is the translational upregulation of c-Mos, a serine/threonine kinase that promotes the activation of the MAP kinase (MAPK) pathway (Schmitt & Nebreda 2002). This is upstream of the polyadenylation of a large subset of mRNAs. In X. laevis, but not mammals, c-Mos is required for complete activation of maturation promoting factor (MPF), comprising a heterodimer of cyclin B and CDC2, which promotes germinal vesicle membrane breakdown (GVBD) and completion of meiosis I. c-mos null mouse oocytes progress normally through meiosis I but exhibit defects during meiosis II, indicating that c-Mos is required for the second meiotic arrest (Gebauer et al. 1994). Indeed, in both mammals and X. laevis c-Mos is required for cytostatic factor (CF) activity which serves to inhibit the anaphase promoting complex (APC), thereby maintaining MPF activity and causing meiosis II metaphase arrest. of intricate and fine-tuned expression patterns, even in 3) joining of the small (40S) ribosomal subunit, 4) the absence of ongoing transcription. scanning of the 50UTR by the 40S subunit and 5) Translational regulation can be divided into two broad recognition of the initiator codon, release of multiple categories: global and specific. Global control affects initiation factors and joining of the large (60S) ribosomal most cellular mRNAs in response to a given signal and is subunit. often mediated by changes in the activities of basal Intriguingly, although translation initiation occurs at translation factors. By contrast, specific regulation affects the 50end of the mRNA, the poly (A) tail at the 30end of only a single or subset of mRNAs in a coordinate manner, the message is also important. Poly(A) tails are bound by normally via sequence elements located within these a family of proteins called poly(A)-binding proteins mRNAs. Global and specific regulation can occur (PABPs) which interact with proteins bound to the 50end, simultaneously to rapidly reprogram protein synthesis bringing the 50-and30ends of an mRNA into proximity. (reviewed in (Spriggs et al. 2008, Yamasaki & Anderson This end-to-end configuration is termed the ‘closed-loop’ 2008)). (illustrated in Fig. 3B), is highly conserved throughout Translation can be divided into three basic steps: evolution (Gallie 1998, Kahvejian et al. 2001) and forms i) initiation, during which many of the required factors the basis for understanding regulation by factors bound are recruited; ii) elongation, whereupon an mRNA is to the 30UTR. decoded by the ribosome and associated factors and iii) termination, when the de novo synthesized mRNA-specific regulation of translation initiation polypeptide and the translational machinery are released. While each of these steps can be regulated, Cap-dependent translation provides multiple points at specific mRNA regulation occurs most frequently at the which initiation can be regulated in an mRNA-specific level of initiation. manner (Gray & Wickens 1998, Scheper et al. 2007). Eukaryotic mRNAs exit the nucleus with a modified Such regulation requires cis-acting elements that are 7-methyl guanosine at the 50end, termed the cap normally located within the 50-and30UTRs, but are structure, and a poly(A) tail of w250 nucleotides at the occasionally found within the main open reading frame. 30end. These features act as the primary determinants of These elements can confer differential regulation to translational initiation efficiency. Cap-dependent mRNAs transcribed from the same gene via their initiation accounts for the majority of cellular translation inclusion/exclusion due to alternative promoter or and although other mechanisms of initiation are also polyadenylation site use and/or splicing. To date the utilized during gametogenesis they are beyond the scope majority of examples of mRNA-specific regulation of this review (Spriggs et al. 2008). This pathway is a during gametogenesis involve 30UTR-mediated control complex process with several mRNA-dependent steps (Radford et al. 2008). 30UTRs act as a repository for that are described in detail in Fig. 3. Briefly, initiation elements that regulate mRNA translation, stability or proceeds with 1) binding of a protein complex to the localization; normally by acting as binding sites for a 50 cap, 2) unwinding of mRNA secondary structure, variety of trans-acting factors. These include miRNA
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Progesterone or LH
AC
G2 PKA Cyclin arrest B1/B4
Cyclin CDC2 B1/B4 P
RINGO/SPY Maternal mRNA translation (inc. via cytoplasmic polyadenylation)
Wee1 Meiosis II CDC2 CDK2 Mos entry P Mos Eg2/ AurA P ERK P CPEB P MEK
P MAPK
P RSK1/2
P MYT1
APC/C
Cyclin Cyclin GVBD/ Metaphase B2/B5 B2/B5 Meiosis I arrest P Pre- CDC2 CDC2 MPF CDC25 P MPF P P
Figure 2 Schematic of the major signalling and gene expression events that regulate vertebrate oocyte maturation. Oocyte maturation is induced by exposure to hormones which initiate complex cascades of kinase/phosphatase activity and translationally regulated gene expression. These highly regulated events facilitate the coordinated completion of meiosis I and entry into meiosis II. The process of oocyte maturation is described in greater detail in Box 2. AC, adenylate cyclase; APC, anaphase promoting complex; AurA, aurora A; CF, cytostatic factor; CPEB, CPE-binding protein; GVBD, germinal vesicle breakdown; MAPK, mitogen-activated protein kinase; MPF, maturation promoting factor; PKA, protein kinase A; RINGO/SPY, rapid inducer of G2/M progression in oocytes/speedy. Events in which an as yet unidentified intermediate may play a role are denoted by dotted arrows. Phosphorylation events are denoted by an encircled P. binding sites or protein binding sites such as cyto- been delineated in a few notable cases. Although plasmic polyadenylation elements (CPEs). It should these studies indicate that translation initiation can be stressed, however, that individual mRNAs often be regulated at almost every step, (Wilkie et al. contain multiple cis-acting elements that, rather than 2003, Radford et al. 2008), most of the characterized acting in a binary manner, confer combinatorial factors are repressors; thus, the mechanism of action of regulatory control over the mRNA (Wilkie et al. 2003). 30UTR bound activators remains largely enigmatic. A further level of complexity is added by the fact that many of the trans-acting factors are themselves part of dynamic multiprotein complexes that can Translation control during oogenesis: the importance of cytoplasmic polyadenylation confer differential regulation to a bound mRNA. While many mRNAs are translationally regulated, relatively One important mechanism for the regulation of mRNAs few of the trans-acting factors have been identified during gametogenesis is via the dynamic modulation and the molecular mechanism of action has only of mRNA poly(A) tail length (Fig. 4). In general, an www.reproduction-online.org Reproduction (2009) 137 595–617
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A B 1 eIF-4G 5′ UTR 7 4A m GpppG AUG AUG eIF-4E 4B 4E
2 4A eIF-4G 4G
m7GpppG 4A AUG 4B eIF-4E 4B Met 3 3 eIF3 eIF-4G 2 40S 1 5 m7GpppG 4A 1A AUG PABP1 PAIP1 eIF-4E 4B UAG AAAAAAA Met 4 2 40S 1 5 1A AUG
Met 5 40S
AUG
60S
Figure 3 Overview of mRNA translation initiation. (A) The mRNA-dependent steps of cap-dependent translation initiation. (1) The eIF4F complex (eIF4A, eIF4E and eIF4G) binds the 50end of the mRNA via the cap-binding protein eIF4E. eIF4G coordinates the binding of eIF4E to the cap and the ATP-dependent RNA helicase activity of eIF4A, which is stimulated by eIF4B. (2) eIF4A helicase activity removes secondary structure within the 50UTR. (3) Removal of secondary structure facilitates small ribosomal subunit (40S) binding at or near the cap. The 40S also carries with it a number of initiation factors; including the initiator tRNA complex (eIF2-GTP-tRNAi), eIF1, eIF1A, eIF5 and eIF3. Multiple interactions, including that between eIF4G and eIF3, may facilitate this step. (4) 40S and its associated factors then ‘scan’ the 50UTR, in a poorly defined process, to locate an appropriate initiator codon (most frequently the first AUG encountered). (5) Initiator codon recognition results in GTP hydrolysis of eIF2.GTP, release of multiple initiation factors and large ribosomal subunit (60S) joining to form the translationally competent 80S ribosome. A number of additional eIFs drive this process. Initiation ends with the Met-tRNAi based paired to the AUG in the P-site of the 80S ribosome, with the A-site being available for delivery of tRNA. For clarity, the function of some initiation factors that are not pertinent to this review have been omitted (for a more detailed review see (Gray & Wickens 1998, Scheper et al. 2007)), and the spatial arrangement of factors does not depict all in vivo interactions. (B) The closed-loop model of translation initiation. PABP interacts with eIF4G, functionally linking the ends of the mRNA via the interaction of eIF4G with the cap-binding protein eIF4E. This interaction increases both cap (panel A, step 1) and poly(A)-binding by the end-to end complex. PABP also interacts with eIF4B and PAIP1, both of which interact with eIF4A; thus PABP may influence unwinding of secondary structure within the 50UTR via eIF4A (panel A, step 2). PAIP1 may also influence eIF3 function, enhancing or stabilizing interaction of the 40S with the mRNA (panel A, step 3). While PABP-eIF4G interactions are the most studied, each of these interactions may play an incremental role in initiation complex stabilization, thereby enhancing various steps of translation initiation. A single molecule of PABP is shown for simplicity. Numbered factors, eIFs. Filled black circle, 50cap. Dotted lines denote lack of interaction between overlapping factors. increase in poly(A) tail length correlates with trans- mechanism that is distinct from nuclear polyadenylation lational activation while a decrease correlates with (Radford et al. 2008). Indeed, enucleation of X. laevis translational silencing. Many X. laevis oocyte mRNAs oocytes does not block this process (Fox et al. 1989). contain 30UTR elements that target the mRNA for rapid Pique et al. (2008) recently estimated that w45% of poly(A) tail shortening following export into the stored mRNAs undergo cytoplasmic polyadenylation- cytoplasm (e.g. cyclin B1 poly(A) length in the dependent regulation during X. tropicalis oocyte cytoplasm of immature oocytes is w30 nucleotides; maturation and that O30% of mouse and human Sheets et al. 1994). Such mRNAs remain stable but are oocyte mRNAs were similarly regulated. Cytoplasmic stored translationally silent until, under permissive polyadenylation is critical for gametogenesis in mouse, conditions, the poly(A) length is increased again. C. elegans, Drosophila and other model organisms and Critically these regulated, and often dramatic, changes also occurs in human oocytes (Gebauer et al. 1994, in poly(A) length occur within the cytoplasm by a Prasad et al. 2008; reviewed in (Radford et al. 2008));
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A B pellucida 3 (ZP3) promoter, the loss of polyadenylation Translationally silent Maximal translational activation of a number of key mRNAs was demonstrated (Racki & Richter 2006). These include growth differentiation 1 A AAAAAA factor 9 (GDF9), a critical folliculogenic growth factor DAZL 2 A A expressed by the oocyte; SMAD5, which functions in the – transforming growth factor (TGF) b signalling pathway; 3 AAA AAAAAA and H1Foo, an oocyte-specific histone 1 variant which is a)DAZL b) DAZL 4 A A AAAAAA essential for oocyte maturation. A progressive decrease Figure 4 Translational activation of silent mRNAs during gametogen- in oocyte and follicle number was observed in these esis. (1) Many mRNAs are activated by cytoplasmic polyadenylation, CPEB-knockdown mice. At the dichtyate stage, a number with some being bound by repressor proteins (3) to prevent low levels of oocyte phenotypes were observed including apopto- of precocious translation prior to activation. Other mRNAs with short sis, abnormal polar bodies and parthenogenetic cell poly(A) tails (2 and 4) are activated without a requirement for division. Additionally, oocyte-granulosa cell interactions cytoplasmic polyadenylation by mRNA-specific translational activators are disrupted leading to oocyte detachment from the such as DAZL family proteins. Many mRNAs contain multiple regulatory elements that facilitate complex patterns of activation, e.g. cumulus granulosa cells and impaired folliculogenesis mRNAs are initially activated in the absence of cytoplasmic and these mice often developed ovarian cysts with age. polyadenylation (panel A) but their translational activity is then Several of the phenotypes associated with these CPEB- maintained or enhanced by subsequent polyadenylation (panel B). knockdown mice have led to the proposal that they may model aspects of human premature ovarian failure but has been most intensively studied during X. laevis syndrome (POF; Racki & Richter 2006). Together, these oocyte maturation. findings indicate that cytoplasmic polyadenylation is In order for stage VI X. laevis oocytes to mature they required at multiple steps during the female meiotic need to exit prophase I-arrest and recommence meiosis, program (recently reviewed in (Belloc et al. 2008)). a process that can be induced by progesterone (Box 2 However, CPEB also functions as a translational and Fig. 2). This requires the translational activation of repressor and loss of mRNA repression may contribute many mRNAs (e.g. c-Mos and cyclin B1) in a highly to these phenotypes, but this remains to be addressed. orchestrated temporal sequence. This is achieved via Interestingly, CPEB expression (and cytoplasmic poly- specific cis-acting elements within their 30UTRs, which adenylation) is not restricted to germ cells but its functions in somatic cells are beyond the scope of this promote cytoplasmic polyadenylation (Belloc et al. review and are detailed elsewhere (Richter 2007). 2008, Radford et al. 2008). The critical requirement for the cytoplasmic poly- adenylation of individual mRNAs for oocyte maturation Sequences required for cytoplasmic polyadenylation was demonstrated in seminal studies in X. laevis and All cytoplasmically polyadenylated mRNAs contain mouse. Ablation of endogenous c-Mos mRNA poly- varying combinations of cis-acting sequences that adenylation in X. laevis oocytes via selective removal of determine the precise timing and extent of their its 30end, resulted in inhibition of c-Mos translation and polyadenylation (reviewed in detail in (Belloc et al. progesterone-induced maturation; both of which were 2008)). CPEs are the best characterized and have been rescued by annealing a prosthetic, polyadenylation- 0 predominantly studied in X. laevis oocytes (McGrew competent 3 end or a prosthetic poly(A) tail to the mRNA et al. 1989). CPEs function in collaboration with the (Sheets et al. 1995, Barkoff et al. 1998). Similarly, hexanucleotide (hex) signal AAUAAA (see (Mandel et al. Gebauer et al. (1994) demonstrated the importance of 2008) for review of nuclear polyadenylation), and both c-Mos polyadenylation for mouse oocyte maturation. elements are binding sites for multiprotein complexes Mouse knock-out/down models have revealed that that can interact and are reviewed in detail elsewhere other stages of mammalian gametogenesis are also (Radford et al. 2008). Briefly, CPEB bound to the CPE(s) directed by this process. By deleting a factor required interacts with cytoplasmic polyadenylation and speci- for the adenylation of many mRNAs (CPE-binding ficity factor (CPSF) bound to the hex. CPEB then recruits protein (CPEB)), a lack of cytoplasmic polyadenylation a cytoplasmic poly(A) polymerase GLD-2 and the was shown to result in the arrest of both male and female poly(A) RNase (PARN) which acts antagonistically. germ cells at the pachytene stage of meiotic prophase I During many oogenic stages, PARN activity exceeds (Tay & Richter 2001). This may be due, at least in part, to that of GLD-2, resulting in deadenylation and trans- the loss of synaptonemal complex protein (Sycp) 1 and lational silencing of the mRNA. Thus, CPEs also play a Sycp3 translation, which correlates with a failure of role in rapid deadenylation and translational silencing of homologous chromosome pairing and resultant meiotic regulated mRNAs as they exit the nucleus. Under failure. When CPEB expression was reduced after permissive conditions (e.g. during oocyte maturation) completion of the pachytene stage of prophase I, via CPEB is phosphorylated and PARN dissociates from expression of an siRNA under the control of the zona the complex, facilitating GLD-2-mediated mRNA www.reproduction-online.org Reproduction (2009) 137 595–617
Downloaded from Bioscientifica.com at 09/26/2021 08:03:02PM via free access 602 M Brook and others polyadenylation. Recent data suggest that PABPs may polyadenylation is thought to exert its effects on interact with polyadenylation complex components, translation largely by recruiting PABPs to the newly raising the possibility that this may facilitate rapid extended poly(A) tails. Consistent with a role of PABP in PABP binding to newly synthesized poly(A) tails to poly(A) tail mediated changes during oogenesis, over- promote the mRNA closed-loop conformation (Fig. 3B) expression of PABP1 in X. laevis oocytes blocks the thereby stimulating translation and protecting against maturation-induced deadenylation and translational PARN-mediated deadenylation (Richter 2007, Radford inactivation of mRNAs that lack CPEs, as well as et al. 2008). inhibiting the recruitment of some CPE-containing CPE-containing mRNAs exhibit varying patterns of mRNAs onto polysomes (Wormington et al. 1996). translational activation during oogenesis; with the A role for PABP in oogenesis is also indicated by early sequence, number and position of CPEs with respect to meiotic defects in PAB-1-deficient C. elegans the hex being important. Recent studies further defined (Maciejowski et al. 2005). rules which determine at what point during X. laevis Cytoplasmic PABPs are evolutionarily conserved from oocyte maturation, and with how many adenosines, a yeast to humans and have multiple roles in translation given CPE-containing mRNA will be polyadenylated and mRNA stability (Table 3; reviewed in (Gorgoni & (reviewed in (Belloc et al. 2008)). Regulation conferred Gray 2004)). Drosophila only encode a single cyto- by CPEs/CPEB can be further modulated by the presence plasmic PABP which, like PABP in budding yeast, is of additional cis-acting elements in the mRNA 30UTR, required for viability, whereas C. elegans encodes two such as the pumilio 2 (PUM2)-binding element (PBE). cytoplasmic PABPs and vertebrate genomes encode PUM2 is a member of the PUM/Fem-3 mRNA-binding multiple cytoplasmic PABP genes (Fig. 5A; Gorgoni & factor (FBF) (PUF) family of RNA-binding proteins which Gray 2004). No vertebrate PABP-deficient phenotypes have well-defined roles in translational repression in the have yet been described and only a handful of non- germ-line of many species (Wickens et al. 2002, Kimble synonymous single nucleotide polymorphisms are & Crittenden 2007). However, both CPEB-mediated documented within human PABP genes, possibly polyadenylation, as well as repression, appears to be reflecting an incompatibility of PABP mutation with augmented by PUM2 in X. laevis oocytes. viability. A number of X. laevis mRNAs are activated by In vertebrates, only the molecular functions of the polyadenylation very early in oocyte maturation, in an prototypical PABP1 (also known as PABPC1), and to a apparently CPE-independent manner. To date, two lesser extent ePABP, have been studied in any detail further cis-acting cytoplasmic polyadenylation elements (Voeltz et al. 2001, Gorgoni & Gray 2004, Wilkie et al. are described; Musashi/polyadenylation response 2005). As few as 12 adenosines are required to bind a elements (PREs) that are bound by Musashi (Charles- single PABP molecule, but each PABP has a footprint of worth et al. 2000, 2004) and the translational control w26 adenosines, binding cooperatively and contigu- sequence (TCS) whose trans-acting factor(s) is unknown ously such that long poly(A) tails may be associated (Wang et al. 2008). It is proposed that these elements with multiple PABPs (reviewed in Gorgoni & Gray function during early oocyte maturation prior to CPE- 2004). PABP1 comprises four highly conserved RNA dependent polyadenylation. The temporal regulation of recognition motifs (RRMs) that exhibit differing specifi- cytoplasmic polyadenylation is a contentious issue cities for RNA sequences and interacting proteins, such since, in most of the cases described to date, PREs and as the translation initiation factor, eIF4G (Figs 3 and TCSs are present in mRNAs that also contain CPEs. 5B); a less well-conserved proline-rich region that However, this may reflect a role of multiple cis-acting functions in cooperative PABP binding to poly(A) elements in the intricate regulation of translation via (Melo et al. 2003) and a C-terminal domain (termed combinatorial control. mRNAs that do not contain CPEs the PABC domain) which exhibits homology to HECT are normally silenced following maturation-induced domains of E3-ubiquitin ligases (Kozlov et al. 2001; germinal vesicle breakdown, via a default pathway in Fig. 5B). Neither the proline-rich nor the PABC domain which their poly(A) tails are removed, further enhancing binds the RNA but both interact with proteins; the latter the reprogramming of translation (Fox & Wickens 1990, binding proteins which contain a PABC-binding domain Varnum & Wormington 1990). called PAM2, such as the PABP-interacting protein 1 (PAIP1; Figs 3 and 5B; Kozlov et al. 2001, Albrecht & Lengauer 2004, Kozlov et al. 2004, Lim et al. 2006). PABPs PABP4, testis-specific PABP (tPABP -PABP2 in mouse The primary function of PABPs is to transduce the signal and PABP3 in human) and ePABP exhibit a similar provided by the poly(A) tail and convey it to the domain structure to PABP1 (Yan g et al. 1995, Feral et al. translational machinery (see Fig. 3B). Indeed, tethering 2001, Guzeloglu-Kayisli et al. 2008), whereas PABP5 PABPs to the 30UTR of non-adenylated reporter mRNAs has neither a proline-rich linker region nor a PABC can functionally replace poly(A) tails in X. laevis oocytes domain (Blanco et al. 2001). Vertebrates also encode an (Gray et al. 2000, Wilkie et al. 2005). Thus, cytoplasmic additional protein, ePABP2, which, although apparently
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predominantly cytoplasmic, is more closely related to the nuclear PABPN1 (Cosson et al. 2004). ePABP2 may, like its nuclear counterpart PABPN1, regulate poly(A) tail A length rather than translation (Good et al. 2004)andis Mm PABP5 beyond the scope of this review. Hs PABP5 The expression patterns of vertebrate PABPs are Xt ePABP Xl ePABP documented to varying degrees. PABP1 is expressed in Mm ePABP a wide variety of tissues in humans, mice and X. laevis Hs ePABP and available evidence suggests that PABP4 mRNA may Mm tPABP also be widely expressed in these species (Kleene et al. Xt PABP1 1994, Gu et al. 1995, Yang et al. 1995, Cosson et al. Xl PABP1 2002; GS Wilkie & NK Gray, unpublished observations). Hs tPABP Hs PABP1 Both PABP1 and PABP4 mRNAs are detected in the testis Mm PABP1 and ovary of humans, mice and X. laevis. Other PABPs Ce PAB-2 appear to be more restricted in their expression. RT-PCR Cb PAB-2 analyses of human PABP5 suggest low-level expression Ce PAB-1 in a variety of tissues, with higher levels being detected Cb PAB-1 in the brain and gonads (Blanco et al. 2001). Mouse Dm PABP Xl PABP4 tPABP mRNA and protein and human tPABP mRNA are Mm PABP4 only expressed in pachytene spermatocytes and round Hs PABP4 spermatids (Kleene et al. 1994, 1998, Kimura et al. Hs hnRNPA1 2009). ePABP mRNA is detected in both mouse and B human oocytes and is downregulated during early embryogenesis (Seli et al.2005, Guzeloglu-Kayisli RRM1 RRM2 RRM3 RRM4 PABC et al. 2008, Sakugawa et al. 2008). ePABP mRNA is also expressed at low levels in mouse testis (Wilkie et al. PAIP1 PABP1 2005) but appears to be more widespread in humans. elF4G DAZL Protein-protein ePABP protein expression has been studied in X. laevis eRF3 interactions oogenesis where a developmental switch between PAIP1 PABP1 and ePABP appears to occur (Cosson et al. Figure 5 PABP family evolution and key protein–protein interactions. 2002). Thus, ePABP is the predominant PABP present (A) Phylogenetic tree based on the sequence of PABP family proteins. during most of oogenesis, and during oocyte maturation The tree is rooted to human hnRNPA1, an RNA-binding protein of the and early embryogenesis when regulated poly(A) tail RRM family. Hs: Homo sapiens, Mm: Mus musculus, Xl: Xenopus changes drive the translational selection of mRNAs laevis, Xt: Xenopus tropicalis, Ce: Caenorhabditis elegans, Cb: Caenorhabditis briggsae, Dm: Drosophila melangaster. PABP4 and (Voeltz et al. 2001). The physiological basis for this ePABP are vertebrate-specific and PABP5 is mammalian-specific. switch to ePABP remains to be determined, although tPABP is mammalian-specific and arose from a PABP1 retro- ePABP stimulates translation analogously to PABP1 transposition event. (B) PABP1 domain structure and protein (Wilkie et al. 2005). interactions with translation factors and DAZL. PABP1 consists of four PABP1 regulates translation at multiple steps and by non-identical RRM domains that have different RNA-binding specifi- multiple mechanisms (Gray et al. 2000, Kahvejian et al. cities. The majority of poly(A)-binding activity is conferred by RRMs 1 and 2. The specificity of RRMs 3 and 4 is less clear but this region has 2005). This is in keeping with the fact that PABP1 been linked to the ability of PABP1 to bind AU-rich sequences. The contains several domains that can stimulate translation structure of RRMs 1 and 2 bound to poly(A) has been solved showing and can interact with numerous translation factors that the RNP motifs, characteristic of RRMs, directly contact RNA (Figs. 3B and 5B). The best-characterized interaction is leaving the opposite face free for protein–protein interactions including between PABP1 and eIF4G, a component of the cap- eIF4G and PAIP1 (Gorgoni & Gray 2004). RRMs 3 and 4 also mediate associated complex eIF4F (Figs 3 and 5B), and this protein–protein interactions (not shown). The C-terminal region of interaction is conserved from yeast to man (Derry et al. PABP is composed of a proline-rich region and the PABC domain; PABP1 homodimerization, and DAZL interaction map to this area. 2006). Interaction of PABP1 with eIF4G is proposed to The PABC motif interacts with a variety of factors, including eRF3 and increase both the poly(A)-binding affinity of PABP1 and PAIP1, via their PAM2 domains. Bioinformatic analyses suggest that the cap-binding affinity of the eIF4F complex (Fig. 3A, PABP1 may associate many additional proteins via PABC–PAM2 step 1), establishing the ‘closed-loop’ mRNP confor- mediated interactions (Albrecht & Lengauer 2004). The region of mation (Fig. 3B). This conformation is believed to be PABP1 that interacts with DAZL is also shown. The mapped region of optimal for translational initiation and ribosomal interaction is depicted by a horizontal line. References: PAIP1 (Craig et al. 1998, Gray et al. 2000, Roy et al. 2002), eIF4G (Imataka et al. recycling. Consistent with this, mutations that disrupt 1998), PABP1 (Melo et al. 2003), DAZL (Collier et al. 2005), eRF3 the PABP1–eIF4G interaction result in compromised (Hoshino et al. 1999). Other experimentally determined protein translational activity (Tarun et al. 1997). PABP1 also interactions are not shown including eIF4B. binds to eIF4B (Bushell et al.2001)andPAIP1 www.reproduction-online.org Reproduction (2009) 137 595–617
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(Craig et al. 1998; Figs 3 and 5B), with both interactions length, PABP function and the DAZL proteins, a protein proposed to promote eIF4A RNA helicase activity which family with critical roles in gametogenesis. aids unwinding of secondary structure within the 50UTR (Fig. 3A, step 2). PAIP1 may also influence eIF3 function (Martineau et al. 2008) which is thought to facilitate DAZL family of proteins the 40S subunit joining step (Fig. 3A, step 3). PABP1 can DAZ, DAZL and BOULE comprise a family of proteins also enhance later steps in translation including 60S (Fig. 6A) that have important roles in gametogenesis. subunit joining (Sachs & Davis 1989, Kahvejian et al. Deleted in azoospermia (DAZ) is located within the 2005) and translation termination. PABP1 regulates azoospermia factor locus (AZFc) on the human termination via an interaction with the eukaryotic Y-chromosome and was first identified as a candidate translation termination factor 3 (eRF3; Hoshino et al. factor underlying diverse azoospermia and oligosper- 1999) and recent work in yeast described a potential mia defects in 5–10% of infertile men (Reijo et al. role for the PAB-1–eRF3 interaction in 40S recruitment; 1995, Reynolds & Cooke 2005). Human DAZL (hDAZL) but existence of this mechanism has not been described and BOULE (hBOULE) are both autosomal and their in vertebrates (Amrani et al. 2008). The basis for the roles in human fertility are less clear. hDAZL SNPs have PABP1-mediated regulation of 60S joining remains been linked to Sertoli cell-only syndrome, oligospermia enigmatic (Kahvejian et al. 2005). By necessity most and POF (Reynolds & Cooke 2005, Fassnacht et al. PABP1 interactions have been studied in isolation and it 2006, Tung et al. 2006a, 2006b). An association is unclear to what extent either a single PABP1 molecule between a lack of hBOULE protein and adult male or a cooperatively bound PABP1 oligomer can support germ cell meiotic arrest was observed (Luetjens et al. multiple interactions with the same or multiple protein 2004); although this does not provide any evidence that partners. Therefore, while significant progress has been hBOULE deficiency is causative. Not all family made, many important questions remain pertaining to members are conserved across species with DAZ the mechanisms of action of PABP1 and the functions of being found in humans and old world monkeys, other PABPs (reviewed in greater detail in (Gorgoni & while invertebrates only encode boule (Fig. 6A). Gray 2004, Derry et al. 2006)). Germ cells are the main site of DAZL family protein Although the amplitude of translational activation expression. However, the mammalian germ cell during oogenesis is related to the length of the poly(A) expression patterns of the DAZL family members are complex, although only DAZL has been detected tail added/number PABPs bound, this relationship is in oocytes (detailed in Table 1; reviewed in detail in complex. Upon injection into X. laevis oocytes, reporter (Reynolds & Cooke 2005)). In humans, mice and X. laevis mRNAs with the same length poly(A) tail but different DAZL expression is detectable in primordial germ cells 50UTRs are translated to differing extents (Gallie et al. (PGCs) and all oogenic stages examined so far (Table 1). 2000) and some endogenous oocyte mRNAs are DAZL has also been reported to be expressed in human activated without changes in poly(A) tail length (e.g. and mouse granulosa cells (Ruggiu et al. 1997, Dorfman Wang et al. 1999)(Fig. 4). Moreover, poly(A) tails of et al. 1999), human theca interna cells (Nishi et al. 1999) sufficient length to support multiple PABP binding do and in the granulosa-luteal cells of human corpus lutea not always confer translational activation. In immature (Pan et al. 2002, 2008), but this remains contraversial. In X. laevis oocytes, for instance, c-Mos mRNA has an invertebrates, DAZL family protein expression is not average poly(A) tail length of 50 nucleotides but is not restricted to the germ cells/gonads with Boule being translated, although reporter mRNAs containing the expressed in Drosophila larval neurons and adult brain same length poly(A) tail are very efficiently translated (Joiner & Wu 2004, Hoopfer et al. 2008). (Sheets et al. 1994). This complexity is likely to be Knock-down of X. laevis DAZL (xDAZL) leads to a mediated, at least in part, via a poorly understood defect in PGC migration and proliferation and thus a loss interplay between trans-acting repressors/activators 0 of both female and male gametes (Houston & King bound to 3 UTR cis-acting elements and the poly(A) 2000). Deletion of mouse Dazl (mDazl) results in a tail/PABP (Fig. 4). For example, repressors may prevent complete loss of female germ cells before birth and a PABP binding to poly(A) tails or may modulate PABP failure to advance past meiotic prophase I in spermato- activity. In this regard, Kim & Richter (2007) recently genesis (Ruggiu et al. 1997, Lin & Page 2005). However, showed that ePABP associates with CPEB in a repressive it should be noted that the timing of male germ cell loss complex in X. laevis oocytes prior to maturation. The appears to vary depending on the genetic background; ePABP–CPEB interaction is subsequently lost in maturing with the loss of male germ cells occurring earlier on an oocytes and ePABP binds the de novo synthesized inbred background (reviewed in Reynolds & Cooke poly(A) tails. However, our understanding has been 2005). Consistent with this, DAZL was recently demon- hampered by the relatively few trans-acting factors that strated to be an intrinsic factor required for germ cell have been identified to date. Recently, we and others entry into meiosis (Lin et al. 2008). Only oogenesis have gained insights into the links between poly(A) tail is affected in worms; loss-of-function mutations in the
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C. elegans Boule ortholog daz-1 and DAZ-1 knock-down critical and evolutionarily conserved role for DAZL in Caenorhabditis briggsae lead to pachytene arrest in family proteins in gametogenesis. the female germline (Karashima et al. 2000)and Phenotypic rescue experiments indicate that different disruption of the hermaphroditic sperm/oocyte switch DAZL-family proteins may contribute to gametogenesis (Otori et al. 2006) respectively. Conversely, loss of by related molecular mechanisms. For instance, ectopic Drosophila boule results in defective G2/M transition expression of xDAZL and hBOULE in Drosophila or during spermatogenesis only (Eberhart et al. 1996). human DAZ (hDAZ) expression in mice can partially Taken together, these observations strongly support a rescue the boule and mDazl null male phenotypes respectively (Houston et al. 1998, Slee et al. 1999, Xu et al. 2003). However, this redundancy is incomplete A Dr Dazl Xt Dazl since many organisms, including mice, encode both Xl Dazl Dazl and Boule, but mouse DAZL (mDAZL) deficiency Mm DAZL results in male infertility even though mouse BOULE Hs DAZL (mBOULE) expression partially overlaps with normal Hs DAZ-2 mDAZL expression during spermatogenic differentiation Hs DAZ-3 (Reynolds & Cooke 2005). While differential expression Hs DAZ-1 Hs DAZ-4 may contribute to this lack of redundancy, different Ce DAZ-1 family members may have both overlapping and distinct Cb DAZ-1 targets and functions. A better understanding of their Dm Boule individual molecular functions and mRNA targets is Mm Boule required to clarify this issue. Hs Boule Hs hnRNPA1
B DAZL family proteins are translational regulators DAZ DAZ DAZL family proteins are identified by the presence of DZIP1 PUM2 DAZAP1 and DAZAP2 two functional domains; RRMs and DAZ domains, the latter of which appears to be unique to this family. RRM DAZ DAZ DAZ DAZ DAZ DAZ DAZ DAZ RRMs are found in many RNA-binding proteins (such as PABPs) which function in processes as diverse as mRNA DAZAP1 and DAZAP2 DAZL splicing, localization, translation and stability. Indeed, PABP Dynein light chain (Dlc) several studies have demonstrated that DAZL family
RRM DAZ proteins are bona fide RNA-binding proteins (Reynolds
DAZL DAZ & Cooke 2005), consistent with a role in nuclear and/or cytoplasmic post-transcriptional gene regulation. The
BOULE / DAZL subcellular localization of DAZL family proteins BOULE changes during gametogenesis and, while DAZL family RRM DAZ proteins may have undefined nuclear functions, it is of PUM2 note that the timing of germ cell loss in outbred male mDazl null mice corresponds to the meiotic stages Figure 6 DAZL family evolution and key protein–protein interactions. during which mDAZL becomes localized to the (A) Phylogenetic tree based on the sequence of DAZL family proteins. The tree is rooted to human hnRNPA1, an RNA-binding protein of the cytoplasm (Reynolds & Cooke 2005, Anderson et al. RRM family. Hs: Homo sapiens,Mm:Mus musculus, Xl: Xenopus laevis, 2007). The importance of a cytoplasmic, rather than Xt: Xenopus tropicalis, Dr: Danio rerio,Ce:Caenorhabditis elegans, nuclear, function was elegantly demonstrated in Droso- Cb: Caenorhabditis briggsae, Dm: Drosophila melangaster. DAZL is phila, wherein nuclear exclusion of Boule did not vertebrate-specific and is derived from the ancestral BOULE gene, which disrupt germ-cell entry into meiosis (Cheng et al. 1998). is conserved from invertebrates to humans (Reynolds & Cooke 2005) and In humans and mice, DAZL is located in the cytoplasm includes the confusingly named nematode DAZ-1 genes. DAZ appears to throughout oogenesis. have arisen from a transposition of the Dazl gene, followed by subsequent gene amplification and modification, and is present in humans and The first link to a role in translation came from genetic old-world monkeys (Saxena et al. 1996). Although the human genome experiments in Drosophila, where Twine/Cdc25A mRNA normally contains four DAZ genes, copy number variation has been translation was found to be defective in boule null flies. reported (Saxena et al. 2000). (B) DAZL family protein domain structures However, it remains unclear whether Boule mediates its and interactions. Family members contain two recognisable motifs, effect directly on the translation of Twine/Cdc25A mRNA a single RRM (except for some DAZ genes) and the characteristic DAZ or indirectly via alterations in the expression of unknown motif, a repeat of a 24 amino acid sequence that is rich in glutamine, proline and tyrosine (which varies between 7 and 24 copies in DAZ). mRNAs upstream of Twine/Cdc25A (Maines & Wasser- The figure depicts all interactions described in vertebrates. The described man 1999). In vertebrates, a translational or mRNA region of interaction is depicted bya horizontal line. See Table 2 for DAZL stability role for DAZL family proteins was intimated by family protein interaction references. the detection of mDAZL, and subsequently exogenously www.reproduction-online.org Reproduction (2009) 137 595–617
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BOULE DAZL DAZ ro n others and Brook M
(2009) Germ cell stage Hs Mm Hs Mm Hs PGC No Xu et al. (2001) No Xu et al. (2001) c/N Reijo et al. (2000), Ruggiu C/N Xu et al. (2001) c/N Reijo et al. (2000) and Xu
137 et al. (2000) and et al. (2001) Anderson et al. (2007) 595–617 C/N Xu et al. (2001) Spermatogonia No Xu et al. (2001) No Xu et al. (2001) and c/N Reijo et al. (2000) and Xu C/N Ruggiu et al. (1997) C/n Huang et al. (2008) Moore et al. (2003) et al. (2001) c/N Reijo et al. (2000)
C Ruggiu et al. (2000) and Lin c/N Reijo et al. (2000) and Xu C/N Xu et al. (2001) et al. (2001) et al. (2001)
Leptotene C Xu et al. (2001) and C Xu et al. (2001) and C Reijo et al. (2000), Ruggiu C Ruggiu et al. (1997), Reijo C/N Xu et al. (2001) Kostova et al. (2007) Moore et al. (2003) et al. (2000), Lin et al. et al. (2000) and Xu et al. (2001) and Xu et al. (2001) (2001)
No Huang et al. (2008)
C Reijo et al. (2000)
Zygotene C Xu et al. (2001), Luetjens C Xu et al. (2001) and C Reijo et al. (2000), Ruggiu C Ruggiu et al. (1997), Reijo No Xu et al. (2001) and Huang et al. (2004) and Kostova Moore et al. (2003) et al. (2000), Lin et al. et al. (2000) and Xu et al. et al. (2008) et al. (2007) (2001) and Xu et al. (2001) (2001) C Reijo et al. (2000) Downloaded fromBioscientifica.com at09/26/202108:03:02PM Pachytene C Xu et al. (2001), Luetjens C Xu et al. (2001), Moore C Reijo et al. (2000), Ruggiu C Ruggiu et al. (1997), Reijo No Xu et al. (2001) and Huang et al. (2004), Tung et al. et al. (2003) and et al. (2000), Lin et al. et al. (2000), Xu et al. et al. (2008) (2006a) and Kostova Tung et al. (2006a) (2001), Xu et al. (2001) (2001) and Tung et al. et al. (2007) and Tung et al. (2006a) (2006a) C Reijo et al. (2000) www.reproduction-online.org
Secondary C Xu et al. (2001), Tung C Xu et al. (2001), Moore C Reijo et al. (2000), Ruggiu C Reijo et al. (2000), Xu et al. No Xu et al. (2001) and Huang spermatocyte et al. (2006a) and et al. (2003) and Tung et al. (2000), Xu et al. (2001) and Tung et al. et al. (2008) Kostova et al. (2007) et al. (2006a) (2001) and Tung et al. (2006a) (2006a) No Luetjens et al. (2004) C Reijo et al. (2000) via freeaccess www.reproduction-online.org Round No Xu et al. (2001), Luetjens No Xu et al. (2001), Moore C Reijo et al. (2000), Xu et al. C Xu et al. (2001) and Tung No Reijo et al. (2000), Xu et al. spermatids et al. (2004), Tung et al. et al. (2003) and (2001) and Tung et al. et al. (2006a) (2001) and Huang et al. (2006a) and Kostova Tung et al. (2006a) (2006a) (2008) et al. (2007) No Lin et al. (2001) No Reijo et al. (2000) C Habermann et al. (1998)
Elongating No Xu et al. (2001), Luetjens No Xu et al. (2001), Moore C Reijo et al. (2000), Xu No Reijo et al. (2000), Xu No Reijo et al. (2000) and spermatids et al. (2004), Tung et al. (2003) and et al. (2001) and Tung et al. (2001) and Xu et al. (2001) et al. (2006a) and Tung et al. (2006a) et al. (2006a) Tung et al. (2006a) Kostova et al. (2007) No Lin et al. (2001) C Habermann et al. (1998)
Mature sperm No Xu et al. (2001), Luetjens No Xu et al. (2001), Moore C Lin et al. (2002) No Ruggiu et al. (1997), Xu C Habermann et al. (1998) et al. (2004) and et al. (2003) and et al. (2001) and Tung Tung et al. (2006a) Tung et al. (2006a) et al. (2006a)
No Xu et al. (2001) and Tung No Reijo et al. (2000) et al. (2006a)
Foetal oogonia n.d No Moore et al. (2003) C Ruggiu et al. (2000) and C Ruggiu et al. (1997) Anderson et al. (2007)
C/N Dorfman et al. (1999) ALadPB eitdtasaini oocytes in mediated-translation PABP and DAZL Primordial n.d No Moore et al. (2003) C Dorfman et al. (1999) C Ruggiu et al. (1997) follicle and Nishi et al. (1999) oocytes
Downloaded fromBioscientifica.com at09/26/202108:03:02PM Pre-antral n.d No Moore et al. (2003) C Dorfman et al. (1999), C Ruggiu et al. (1997) follicle Nishi et al. (1999) oocytes and Moore et al. (2003) Reproduction Antral follicle n.d No Moore et al. (2003) C Dorfman et al. (1999) C Ruggiu et al. (1997) oocytes and Nishi et al. (1999)
Being Y-chromosomal hDAZ is not expressed in ovary. n.d., not determined; No, not observed in immunohistochemistry; C, exclusively cytoplasmic localization; N, exclusively nuclear
(2009) localization; C/N, detected in both compartments; C/n, predominantly cytoplasmic localization; c/N, predominantly nuclear localization. Where conflicting reports exist these are presented on individual lines; Hs, Homo sapiens; Mm, Mus musculus. 137 595–617 607 via freeaccess 608 M Brook and others expressed zebrafish DAZL (zDAZL), on actively translat- vertebrate genomes; mRNAs with a 30UTR that contains ing polyribosomes (polysomes; Tsui et al. 2000a, 2000b, multiple binding sites occur much less frequently. Maegawa et al. 2002). Efforts to identify in vivo mRNA targets of mammalian Direct evidence supporting a translational role for DAZL family proteins utilized varied approaches but DAZL family proteins came from two sets of obser- have been mainly restricted to mDAZL (reviewed in vations. First, zDAZL upregulated reporter protein (Reynolds & Cooke 2005)) and have identified multiple synthesis in an in vitro translation assay (Maegawa putative targets (Jiao et al. 2002, Reynolds et al. 2005, et al. 2002). Second, tethering of DAZL family members 2007). These studies focused on testis-expressed mRNAs to the 30UTR of reporter mRNAs microinjected into but it is likely that at least a subset of the identified X. laevis oocytes provided evidence that xDAZL, mRNAs are regulated during oogenesis. mDAZL, hDAZL, hDAZ and hBOULE exhibit a con- Mouse vasa homolog (Mvh) and Sycp3 mRNAs were served and robust ability to stimulate the translation of isolated by co-immunoprecipitation with mDAZL from mRNAs to which they were bound. This suggested a UV-crosslinked mouse testis extracts (Reynolds et al. role in mRNA-specific, rather than global, regulation 2005, 2007). The male phenotypes of Mvh null and of translation (Collier et al. 2005). It is of note that Sycp3 null mice correspond to distinct blocks in meiotic this functional conservation occurs despite the relatively prophase I, reminiscent of the final block in the mDazl low sequence homology between some of these null mice (Tanaka et al.2000, Yua n et al.2000). proteins outside the RRM and DAZ domains. Finally, Combinations of in vitro RNA-binding assays and the 30UTRs from two potential mDAZL target mRNAs translation reporter assays in injected X. laevis oocytes indicated that mDAZL could regulate the translation of conferred DAZL-dependent translational regulation to 0 reporter mRNAs, in microinjected X. laevis oocytes, and reporters containing the 3 UTR from these mRNAs. the levels of the protein products of these endogenous At least for SYCP3, stimulation was dependent on the target mRNAs were reduced in the remaining germ presence of intact mDAZL-binding sites. Importantly, cells in testis of mDazl null mice (see below; Reynolds MVH and SYCP3 protein levels were significantly reduced in the surviving germ cells of mDazl null testis et al. 2005, 2007). (5 or 7 days post-partum respectively), implicating these mRNAs as the first physiological targets of a vertebrate mRNA targets of DAZL family protein-mediated DAZL protein (Reynolds et al. 2005, 2007). regulation of translation However, MVH expression is dispensable for normal mouse oogenesis (Tanaka et al. 2000). Thus, while Mvh The phenotypes associated with the loss of DAZL family mRNA may be regulated by mDAZL in oocytes, the loss function suggest that the targets of DAZL-mediated of its translation does not underlie the defective translational regulation are likely to be mRNAs that oogenesis in mDazl null mice. In Sycp3 null female encode proteins with key functions in oogenesis and/or mice, oogenesis and folliculogenesis progress to spermatogenesis. Initial studies indicated that DAZL completion but the mature oocytes exhibit a high exhibited a general affinity for poly(U) RNA and degree of aneuploidy and a resultant failure of suggested that the affinity may be increased for poly(U) embryogenesis (Yuan et al.2002). The lack of a interspersed by G or C residues (Venables et al. 2001). correlation between the female phenotypes of the These studies defined a loose consensus sequence, mDazl null and Sycp3 null mice indicates that UUU[G/C]UUU, which was later refined to GUUC defective Sycp3 translation is not the primary lesion and U2–10[G/C]U2-10 for zDAZL (Maegawa et al. 2002) leading to the loss of germ cells in mDazl null females, and mDAZL (Reynolds et al.2005) respectively. but does not exclude DAZL-mediated Sycp3 translation Tethered-function and reporter mRNA studies in X. laevis contributing to the production of viable female oocytes (Collier et al. 2005) and zDAZL-transfected cells gametes. It would be desirable to generate a con- respectively (Maegawa et al.2002)suggestthat ditional mDazl null mouse, to induce mDAZL defici- functional DAZL-binding sites were likely to be located ency during later stages of oogenesis and thereby 0 in 3 UTRs of target mRNAs. Furthermore, the tethering of facilitate the study of the roles of putative mDAZL multiple molecules of DAZL stimulates translation to a target mRNAs; for instance during the diplotene arrest greater extent than tethering of a single DAZL molecule; and maturation of oocytes. suggesting that multiple DAZL-binding sites may be Studies aimed at identifying human mRNA targets of required for efficient translational activation of an mRNA DAZL family proteins have proposed CDC25 and (Collier et al. 2005). Consistent with this, several DAZL severe depolymerization of actin 1 (SDAD1)as target mRNAs contain multiple DAZL-binding motifs putative targets. Cdc25 was first suggested as a Boule (Reynolds et al. 2005, 2007) and identification of such target mRNA in Drosophila (Maines & Wasserman 30UTR motif clusters may prove important in identifying 1999), subsequently as a mDAZL target mRNA in bona fide target mRNAs. While the DAZL-binding mouse (Venables et al. 2001, Jiao et al. 2002)and consensus occurs relatively frequently throughout CDC25 protein was absent in testicular biopsies from
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Downloaded from Bioscientifica.com at 09/26/2021 08:03:02PM via free access DAZL and PABP mediated-translation in oocytes 609 men with reduced hBOULE expression (Luetjens et al. exist for the function of DAZL family proteins. Sucrose 2004). However, studies have disagreed regarding gradient analysis of translation intermediates from which CDC25 isoform is the putative target mRNA microinjected X. laevis oocytes revealed that mDAZL and regarding the location of the binding sequence for regulates translation initiation (Collier et al. 2005), DAZL family members within the mRNA, although similar to characterized mRNA-specific repressors; this disparity may be, in part, the result of species thereby raising the possibility that DAZL influences differences (Maines & Wasserman 1999, Venables initiation factor function. et al. 2001, Jiao et al. 2002, Maegawa et al. 2002). A conserved interaction between DAZL family Nonetheless, the potential for DAZL-mediated members and both PABP1 and ePABP was detected regulation of CDC25 translation warrants further in vivo (Collier et al. 2005; Fig. 6B). Importantly, several study since Cdc25b null female mice are sterile lines of evidence demonstrated protein-protein (Lincoln et al. 2002). SDAD1 was identified in a interactions between DAZL family members and yeast-based screen that recovered mRNAs associated PABP1 or ePABP (Table 2), rather than simply detecting with both human PUM2 (hPUM2) and hDAZL (Fox 0 DAZL and PABP associated with the same mRNA, et al. 2005). hDAZL binds to the SDAD1 mRNA 3 UTR thereby implicating PABP1 and ePABP as attractive in vitro but, to date, it is not known whether hDAZL candidates for DAZL-regulated initiation factors. regulates SDAD1 mRNA translation in vitro or in vivo. Two further observations support the hypothesis that To date, no vertebrate DAZL mRNA targets have been a PABP–DAZL interaction is critical for DAZL family definitively identified in female germ cells and a proteins to stimulate translation. First, deletion of the concerted effort is required to redress this lack of PABP interaction site, but not other regions, within knowledge, in order to better understand the role of mDAZL completely abrogated its ability to stimulate hDAZL in human fertility. However, a bona fide DAZL translation (Collier et al. 2005). This loss of activity was family target mRNA with a role in oogenesis has been independent of mDAZL RNA-binding activity since the identified in the hermaphroditic worm C. elegans. protein was artificially tethered to the reporter mRNA. Translation of FBF mRNAs, which encode proteins Second, the relative ability of mDAZL to activate required for germline stem cell maintenance and the reporter mRNA translation is reduced when the mRNA sperm-oocyte switch, is enhanced by DAZ-1 binding is polyadenylated; indicating that the amplitude of during the switch to oogenesis (Otori et al. 2006). mDAZL-mediated translational activation is altered In vertebrates, a potential oocyte target mRNA was when the mRNA can recruit multiple PABPs via the suggested in X. laevis oocytes. RINGO/SPY activates poly(A) tail (Collier et al.2005). However, the CDK2, initiating a phosphorylation cascade that is determination of the extent to which PABPs are critical for oocyte maturation (Box 2 and Fig. 2). In prophase I-arrested oocytes RINGO/SPY mRNA is required for DAZL function in vertebrate oogenesis translationally repressed by a complex containing will require the genetic confirmation of a role for the PUM2 (xPUM2), xDAZL and ePABP. RINGO/SPY DAZL-PABP interaction. Interestingly, the C. elegans translation is required prior to the onset of CPE- DAZ-1 loss-of-function phenotype is highly reminiscent mediated cytoplasmic polyadenylation and its mRNA of the C. elegans PAB-1-deficient phenotype, both does not contain CPEs. When maturation is triggered exhibiting early meiotic blocks in the female germline xPUM2 exits the complex and RINGO/SPY translation (Maciejowski et al. 2005, Maruyama et al. 2005). is activated, presumably in an ePABP and/or xDAZL- The apparent requirement for an interaction with dependent manner (Padmanabhan & Richter 2006). PABP, a known translation initiation factor, provides a A demonstration that RINGO/SPY translational activa- model for DAZL function. In this model, DAZL bound to a 30UTR recruits PABP which, in turn, interacts with tion is mediated by xDAZL in X. laevis would raise 0 the possibility that it is similarly regulated during 5 end-associated factors to enhance the assembly of mammalian oogenesis. the closed-loop mRNP conformation (Fig. 7, see also Fig. 3B). The interaction of DAZL with the C-terminal region of PABP should permit PABP to simultaneously Mechanism of DAZL-mediated translational scaffold interactions with the key factors required to stimulation promote translation initiation, such as eIF4G (Fig. 5B). The observation that multiple DAZL family members However, it remains to be examined whether PABP from a variety of species can stimulate the translation of maintains all its interactions with translation factors specific mRNAs suggests that this conserved function is when complexed with DAZL. Nor is it known which critical to their roles in oogenesis (Collier et al. 2005, step(s) of initiation DAZL regulates as PABP has Reynolds et al. 2007). Therefore, it is important to pleiotropic effects on initiation. Moreover, this model understand the mechanism(s) by which they stimulate does not rule out the possibility that other DAZL- translation. Since the function of mRNA-specific trans- interacting factors may modulate or co-operate with lational activators is poorly understood, few paradigms PABP to promote DAZL-mediated stimulation. www.reproduction-online.org Reproduction (2009) 137 595–617
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Table 2 Available evidence for best-characterized DAZL-interacting proteins.
Interaction Protein Interacts with mapped? Methods used RNase used? References
Hs DAZL Hs DAZ Yes Y2H, GSTlys Tsui et al. (2000a) and Moore et al. (2003) Xl PABP1 No Y2H Collier et al. (2005) Hs DAZAP1 Yes Y2H, GSTlys RNase A Tsui et al. (2000a, 2000b) Hs DAZAP2 Yes Y2H, GSTlys Tsui et al. (2000a, 2000b) Hs BOULE Yes Y2H Urano et al. (2005) Hs PUM2 No Y2H* Moore et al. (2003)
Mm DAZL Xl PABP1 Yes Y2H Collier et al. (2005) Xl ePABP Yes oCoIP RNase 1 Collier et al. (2005) Mm Dlc Yes Y2H, GSTlys, oCoIP, eCoIP Lee et al. (2006) Mm DAZL Yes Y2H, GST Ruggiu & Cooke (2000) Hs DAZ No Y2H Ruggiu & Cooke (2000)
Hs DAZ Hs DAZ Yes GSTlys Tsui et al. (2000a, 2000b) Hs PUM2 Yes Y2H, oCoIP Moore et al. (2003) Hs DZIP1 Yes Y2H, oCoIP Moore et al. (2003, 2004) Hs DAZAP1 Yes Y2H, GSTlys RNase A Tsui et al. (2000a) Hs DAZAP2 Yes Y2H, GSTlys Tsui et al. (2000a) Hs DZIP2 No Y2H, oCoIP Moore et al. (2003, 2004) Xl PABP1 No Y2H Collier et al. (2005) Hs BOULE No Y2H Moore et al. (2003)
Hs BOULE Hs BOULE Yes Y2H, oCoIP Urano et al. (2005) Hs PUM2 Yes Y2H, oCoIP Urano et al. (2005) Xl PABP1 No Y2H Collier et al. (2005)
Xl DAZL Xl PABP1 No Y2H, oCoIP, eCoIP RNase 1 Collier et al. (2005) Xl ePABP No eCoIP, Y2H RNase 1 Collier et al. (2005) Xl PUM2 No oCoIP RNase A Padmanabhan & Richter (2006)
Ce DAZ-1 Ce CPB-3 No Y2H, oCoIP, IHC Hasegawa et al. (2006)
Yeast two-hybrid (Y2H) analysis is frequently provided as evidence of a direct protein interaction but interactions can, in some cases, be bridged by endogenous yeast proteins or RNA. * indicates yeast-based screen with multiple components. GST pull-downs (GST) utilizing recombinant proteins purified to homogeneity indicate direct protein–protein interactions. When recombinant proteins are used to pull-down proteins from cell lysates or cell-free translation extracts (GSTlys) the use of RNase is required to distinguish between direct- and fortuitous RNA-mediated interactions. Likewise, other proteins can also bridge such interactions. Co-immunoprecipitation experiments are divided into those examining endogenous proteins (eCo-IP) or studies utilizing overexpressed proteins (oCo-IP). Co-immunoprecipitations performed in the absence of RNase cannot distinguish whether a complex is mediated by protein–protein interactions or whether the proteins are merely bound to different parts of the same mRNA. Immunohistochemistry (IHC) can reveal the presence of potential partners within the same cell or cellular compartment, thus raising the possibility of interaction, but does not provide any evidence of interaction. RNase 1 cuts between all nucleotides and so liberates PABPs from poly(A) RNA. RNase A cuts 30 to uridine and cytosine and will leave stretches of RNA including poly(A) tails intact. Interactions are only listed once.
DAZL interacting proteins and other roles of DAZL in functions of these proteins (Table 3) may provide insight post-transcriptional regulation in the cytoplasm into their potential roles in DAZL-mediated regulation. The recently defined role of DAZL family proteins as However, little is actually known regarding their in vivo translational activators does not preclude them from functions with DAZL. Additional partners are also having additional translational/non-translational func- described for which no obvious functional role in tions within the cytoplasm and/or nucleus. Indeed, many DAZL-mediated regulation can be ascribed: DAZAP-2 mRNA-binding proteins interact with different partners (Tsui et al. 2000a, 2000b) and DZIP1, 2 and 3 (Moore in the same cell, as well as in different cell types or et al. 2004). Table 2 summarises the evidence for the developmental stages, to perform different functions best-characterized interactions with DAZL proteins. (Abaza & Gebauer 2008). Thus, the composition of The PUF family protein PUM2 is expressed in human, DAZL-containing complexes may change throughout mouse and X. laevis oocytes and is also highly expressed gametogenesis in order to enable reprogramming of in human and mouse PGCs, gonocytes and spermata- protein synthesis. gonia and at lower levels in primary and secondary A number of DAZL family-interacting proteins have spermatocytes (Moore et al. 2003, Xu et al. 2007). been identified (Fig. 6B and Table 2) including PUM2, xPUM2 acts as a translational repressor via binding to dynein light chain (DLC) and DAZL-associated protein 1 PBEs (see sequences required for cytoplasmic polyade- (DAZAP-1). The previously characterized molecular nylation), and also contributes to regulated cytoplasmic
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interfering with the poly(A) tail, rather than xDAZL, as AUG 4E described for Drosophila pumilio (Wreden et al. 1997). It also remains possible that xDAZL is an active 4A 4G component of the repression complex. Thus, it is unclear whether xPUM2 is repressing the stimulatory action of xDAZL, whether xDAZL is an active component of the 4B repressive complex or even whether xDAZL is involved 3 in the subsequent activation of this mRNA. It has also been suggested that PUM2/DAZL PABP1 PAIP1 interactions may affect RNA-binding. Human PUM2 DAZL UAG (hPUM2) interacts with hBOULE and hDAZL (Moore A et al. 2003, Urano et al. 2005) and it has been suggested Figure 7 Model for DAZL-mediated translational stimulation of target that hPUM2 may aid the recruitment of these proteins mRNAs. DAZL family members bind to 30UTR sequence elements and to mRNAs. Consistent with this, RINGO/SPY mRNA in directly recruit PABP molecules via protein-protein interactions. Like X. laevis does not contain putative DAZL binding sites cytoplasmic polyadenylation, this is predicted to increase end-to-end in its 30UTR (Urano et al. 2005). Conversely, it has complex formation (see Fig. 3B), leading to enhanced ribosomal subunit been suggested that the mRNA targets of PUM2 may be recruitment (not shown). However, the molecular mechanism by which this is achieved remains to be determined and it is unclear whether altered as a function of the interaction with specific DAZL-bound PABP maintains all its translation factor interactions. DAZL family proteins (Urano et al. 2005). While this activation does not require changes in polyadenylation, in While data supports a role for xPUM2 in X. laevis some cases polyadenylation may contribute to increased activation of a oogenesis (Padmanabhan & Richter 2006), it remains DAZL-bound target mRNA or contribute to the maintenance of its unclear whether any of its functions are mediated via activated state (Fig. 4). Target mRNAs bound by multiple DAZL molecules may recruit multiple PABPs resulting in a higher degree of xDAZL. Genetic evidence for a physiologically import- translational activation. PABPs may also be bound to the (short) poly(A) ant role in mammalian oogenesis is absent since Pum2 tail. Numbered factors, eIFs. Filled black circle, 50cap. Dotted lines null mice are fertile. However, male mice do display a denote lack of interaction between overlapping factors. significant reduction in testis size (Xu et al. 2007) and the lack of ovarian phenotype could be due to a level of polyadenylation (Table 3)(Nakahata et al. 2001, 2003). redundancy with mouse PUM1. Thus, further work is In immature X. laevis oocytes xPUM2 regulates RINGO/ required to clarify the functional and physiological SPY translation (see mRNA targets), and interacts with consequences of DAZL–PUM2 interactions. xDAZL that is also bound to this mRNA (Padmanabhan & mDAZL also interacts in vitro with dynein light chain, Richter 2006). The association of xPUM2, xDAZL and a component of the microtubule-associated dynein– ePABP with translationally repressed RINGO/SPY mRNA dynactin motor complex which has an important role in led to the proposal that xPUM2 may interfere with the mRNA localization (Lee et al. 2006). Indeed, when translation activation function(s) of xDAZL/ePABP. mDAZL was ectopically expressed in cultured somatic However, the polyadenylation status of RINGO/SPY cells, it was able to regulate the cytoplasmic distribution mRNA has not been determined and xPUM2 may act by of reporter mRNAs containing either the CDC25C (but
Table 3 Molecular functions of DAZL interacting proteins.
DAZL-interacting Experimental evidence for protein Molecular function(s) DAZL-dependent function PABPs i) Translation initiation factor i) Tethered function assays; Collier et al. (2005) ii) mRNA stability and deadenylation iii) Translational repressor iv) Nonsense-mediated mRNA decay
PUM2 i) Translational repressor of CPE-dependent translation – ii) Translational activator of CPE-dependent translation iii) Direct translational repressor
Dynein light chain i) Transport of mRNAs and proteins along microtubules i) Intracellular mRNA transport studies; Lee et al. (2006)
DAZAP-1 ? –
DAZAP-2, DZIP1-3 ? –
The described molecular functions are from a variety of species, some of which have multiple family members. These functions are independent of an interaction with DAZL family members. Experimental evidence for DAZL-mediated function refers to experiments aimed at directly testing the function of these proteins when participating in complexes with DAZL. www.reproduction-online.org Reproduction (2009) 137 595–617
Downloaded from Bioscientifica.com at 09/26/2021 08:03:02PM via free access 612 M Brook and others not CDC25A), TPX1 or MVH 30UTRs (see DAZL targets). mRNA abundance may be a direct consequence of germ While mRNA localization is heavily linked to trans- cell loss or an indirect consequence of mDAZL lational control in organisms whose oocytes contain deficiency. Nonetheless, changes in mRNA stability are germ-plasm, the role of this process in mammalian often linked to changes in mRNA translation. Thus, oocytes is less well explored. It would be interesting to DAZL-mediated changes in the translation of target determine the extent of mDAZL involvement in the mRNAs may alter their stability, but no evidence localization of mRNAs that it subsequently activates currently supports a distinct role in mRNA stability. in vivo. Moreover, localized mRNAs are normally repressed prior to their translation, which could involve partners such as PUM2 or even DAZAP-1. A model for DAZL as a translational activator of mRNAs The mRNA-binding protein DAZAP-1 (also known as during oogenesis proline-rich protein (PRRP)) is widely expressed in human Observations in C. elegans and mouse suggest that DAZL and mouse, with high-level expression in testis (Tsui et al. may function at various defined times during gameto- 2000a, 2000b, Dai et al. 2001, Kurihara et al. 2004, Hori genesis (Collier et al. 2005, Reynolds & Cooke 2005, et al. 2005, Pan et al. 2005). Where investigated, DAZAP- Reynolds et al. 2007). DAZL function may change during 1 appears to interact with DAZ motifs, a region important the complex, multistage oogenesis program in order to for the polysomal localization of DAZL, suggesting that it regulate different aspects of mRNA metabolism; changes could contribute to DAZL-activated translation or which may depend on protein partner interactions. modulate this function by preventing the binding of However, to date, only a role in activating mRNA other proteins to this region. Interestingly, in this regard, translation has been demonstrated. Cytoplasmic poly- human DAZAP-1-associated DAZ does not interact with adenylation is an important mechanism for regulating PABP in vitro (Morton et al. 2006), although the minimal the translation of a large number of oligoadenylated binding site for PABP does not include the DAZ motif. mRNAs, but not all mRNAs appear to require poly- Thus, while no role in translation has been established adenylation for translational activation (Radford et al. for DAZAP-1, these studies raise the possibility that 2008). While loss of repression could contribute to the DAZAP-1 may repress, activate or modulate DAZL activation of these mRNAs, it appears likely that family-mediated translation. activating proteins may be required to compensate for DAZAP-1 may also have other roles. Human DAZAP-1 their short poly(A) tail status (Wang et al. 1999). Since is a nucleocytoplasmic shuttling protein (Lin & Yen 2006) DAZL family proteins appear to be mRNA-specific and its X. laevis ortholog, PRRP, associates with mRNA translational regulators that stimulate efficient translation localization elements in Vg1 and VegT mRNAs (Zhao of mRNAs with short poly(A) tails, it was suggested that et al. 2001). However, it is unclear whether DAZAP-1 the binding of DAZL proteins (and their associated plays an active role in mRNA localization and its role on PABPs) may be one mechanism by which such mRNAs these mRNAs appears to be independent of xDAZL. The can be activated (Collier et al. 2005, Reynolds et al. wide expression pattern of DAZAP-1 also suggests that it 2005, 2007; Figs 4 and 7). This would allow the frequently functions independently of DAZL proteins. activation of small subsets of mRNAs, for instance at DAZAP-1 is a substrate of the ERK2 kinase, raising the times that do not coincide with waves of cytoplasmic possibility that its interaction with protein partners may polyadenylation. This hypothesis does not preclude the be subject to regulation by phosphorylation. Consistent DAZL-mediated translational activation of mRNAs with with this notion, phosphomimetic forms of human longer poly(A) tails but, rather, predicts that the DAZAP-1 exhibit reduced DAZ binding activity in vitro magnitude of their stimulation would be reduced. (Morton et al. 2006). It seems unlikely that there is no link between DAZL- Recently, Hsu et al. (2008) showed that most Dazap-1 mediated translational activation and cytoplasmic poly- null (or hypomorphic) mice die perinatally due to adenylation. Indeed, the cytoplasmic polyadenylation of growth defects, indicating roles for DAZAP-1 in normal some DAZL family target mRNAs may be required for growth and development. The few surviving DAZAP-1 their maximal translational activation (Fig. 4). For hypomorphic male progeny have no post-pachytene instance, translation of Sycp3 is attenuated in both spermatocytes indicating a role for DAZAP-1 in sperma- mDazl null and Cpeb null mouse germ cells. Sycp3 togenesis. However, Dazap-1 null mice exhibit apparently mRNA contains both mDAZL binding sites and a CPE normal oogenesis, indicating that an mDAZL–DAZAP-1 and has a short poly(A) tail (w20 As) in Cpeb null interaction is not an absolute requirement for mouse oocytes, indicating that CPEB-dependent cytoplasmic oogenesis, although DAZAP-1 is normally expressed in polyadenylation is required for full translational acti- the ovary. vation of SYCP3 expression. The mDAZL binding site(s) Finally, a role for DAZL family proteins in regulating in the Sycp3 30UTR overlaps with the CPE and, although mRNA stability may be indicated by the decrease in it has not been formally excluded that both sites can be abundance of a subset of mRNAs in mDazl null mouse occupied simultaneously, the inability to co-immuno- testis (Maratou et al. 2004). However, these changes in precipitate CPEB and mDAZL makes this unlikely
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(Reynolds et al. 2007). The translation of Sycp3 may be short poly(A) tail in CPEB-deficient mice. While initially activated by mDAZL which is then either molecular studies support an important role of PABP in replaced or further activated by CPEB to maintain and/ DAZL-mediated activation, the physiological role of this or promote Sycp3 translation. In contrast, in C. elegans, interaction remains to be clarified. The targeted mutation an interaction between the BOULE ortholog DAZ-1 and of the PABP-binding region of DAZL by genetically the CPEB ortholog CPB-3 has been detected (Hasegawa disrupting this interaction in a model organism, such as et al. 2006) raising the possibility that DAZL family the mouse, would determine the extent to which DAZL proteins can activate translation both directly via DAZL/ utilises PABP for translational activation. Such a model PABP interactions and indirectly by facilitating cyto- would also provide insight into some of the roles of plasmic polyadenylation. However, no DAZL family PABPs during gametogenesis. Ultimately, further members have yet been shown to promote polyadenyla- definition of the molecular mechanism of DAZL- tion and, given the dual role of CPEB in repression as mediated stimulation may require a detailed under- well as polyadenylation, the functional consequences of standing of the mechanisms by which PABP activates the this interaction remain unclear. Greater insight into the initiation pathway and which of these activities is molecular mechanisms of DAZL action and its relation- modulated by DAZL. ship with other protein complexes will be required to However, PABPs are also likely to have other essential understand how regulatory elements and associated roles in oogenesis, including the translational activation factors, both individually and in combination, function of cytoplasmically polyadenylated mRNAs and both to achieve the changes in gene expression required to default and adenosine/uridine-rich element (ARE)- complete oogenesis. mediated deadenylation of mRNAs. Expression of multiple PABPs within certain cell types, including X. laevis oocytes, raises the possibility that PABPs have Perspectives both overlapping and distinct roles during oogenesis. It is While other putative functions remain to be elucidated, therefore tempting to speculate that PABPs may share it appears that DAZL proteins fulfil their roles in some of their poly(A)-mediated functions but differ in oogenesis, at least in part, by activating the translation their ability to control specific mRNAs, for instance via of target mRNAs. However, it is appealing to speculate proteins such as DAZL. Generation of PABP-deficient that DAZL may also participate in complexes that vertebrate models will be crucial to increase our localise and repress target mRNAs prior to their understanding of the molecular and physiological roles activation at defined times during oogenesis. The extent of this multi-functional protein family in gametogenesis. to which other family members may share these Moreover, it is clear that the study of PABPs will be functional properties also remains to be determined, relevant to other areas of reproductive and non- but while DAZ and BOULE mRNA targets may overlap reproductive biology. with those of DAZL in spermatogenesis this appears The study of DAZL function may also have unforeseen unlikely in vertebrate oocytes. implications because DAZL-mediated recruitment of A greater understanding of the roles of DAZL proteins PABP in a poly(A)-independent manner raises the 0 during vertebrate oogenesis is hampered by the current question of how many other 3 UTR-binding proteins dearth of identified female DAZL target mRNAs, function analogously. The idea that such a mechanism although further study of RINGO/SPY in X. laevis may be more widespread is supported by the recent appears warranted. This mRNA is activated early in observation that proteins such as BRCA1 similarly utilise maturation, lacks CPEs, is bound by complexes PABP (Dizin et al. 2006); thus, studies of DAZL may containing xDAZL and is critical for oocyte maturation. provide a paradigm for understanding the function of The DAZL binding consensus sequence needs to be other translational activators in oocytes as well as other further defined prior to its use in bioinformatic searches cell types. for putative target mRNAs. Moreover, these searches may In conclusion, defining the roles, mechanisms and require a clearer understanding of how these elements RNA targets of these interrelated DAZL and PABP function together with, or independently of, other families in gametogenesis may ultimately identify control sequences such as CPEs and PBEs. Furthermore, potential sites of therapeutic intervention in infertility. it will be important to determine whether DAZL- However, it will be important to ascertain to what interacting proteins alter the RNA-binding specificity of extent these animal studies accurately model human DAZL proteins. Ultimately, the functional definition and reproductive disorders. in vivo validation of DAZL target mRNAs will require a combination of molecular and genetic studies in models such as Xenopus and mouse. Declaration of interest In oogenesis, DAZL-mediated translation may pre- The authors declare that there is no conflict of interest that dominantly play a role in the activation of mRNAs with could be perceived as prejudicing the impartiality of the short poly(A) tails. Consistent with this, Sycp3 has a research reported. www.reproduction-online.org Reproduction (2009) 137 595–617
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Funding Cosson B, Couturier A, Le Guellec R, Moreau J, Chabelskaya S, Zhouravleva G & Philippe M 2002 Characterization of the poly(A) N K G is the recipient of MRC GIA and a MRC Senior Non- binding proteins expressed during oogenesis and early development of Clinical Fellowship and Wellcome Trust project grant funding. Xenopus laevis. Biology of the Cell 94 217–231. Cosson B, Braun F, Paillard L, Blackshear P & Beverley Osborne H 2004 Identification of a novel Xenopus laevis poly (A) binding protein. Biology of the Cell 96 519–527. Acknowledgements Craig AW, Haghighat A, Yu AT & Sonenberg N 1998 Interaction of polyadenylate-binding protein with the eIF4G homologue PAIP We would like to thank Brian Collier for his initial contributions enhances translation. Nature 392 520–523. to this review, other members of the laboratory for their helpful Dai T, Vera Y, Salido EC & Yen PH 2001 Characterization of the mouse comments and Gavin S Wilkie (G S W) for the use of his Dazap1 gene encoding an RNA-binding protein that interacts with unpublished data. We are grateful to Ian Adams, Richard infertility factors DAZ and DAZL. BMC Genomics 2 6. Anderson, Andrew Childs, Howard Cooke, Henry Jabbour, Derry MC, Yanagiya A, Martineau Y & Sonenberg N 2006 Regulation of poly(A)-binding protein through PABP-interacting proteins. Cold Spring Alan McNeilly, Philippa Saunders and Tom Van Agtmael for Harbor Symposia on Quantitative Biology 71 537–543. their critical reading of the manuscript. 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