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The APC/C in Female Mammalian Meiosis I

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The APC/C in Female Mammalian Meiosis I REPRODUCTIONREVIEW The APC/C in female mammalian meiosis I Hayden Homer1,2 1Mammalian Oocyte and Embryo Research Laboratory, Cell and Developmental Biology, UCL, London WC1E 6BT, UK and 2Reproductive Medicine Unit, Institute for Women’s Health, UCLH Elizabeth Garrett Anderson Wing, London NW1 2BU, UK Correspondence should be addressed to H Homer; Email: [email protected] Abstract The anaphase-promoting complex or cyclosome (APC/C) orchestrates a meticulously controlled sequence of proteolytic events critical for proper cell cycle progression, the details of which have been most extensively elucidated during mitosis. It has become apparent, however, that the APC/C, particularly when acting in concert with its Cdh1 co-activator (APC/CCdh1), executes a staggeringly diverse repertoire of functions that extend its remit well outside the bounds of mitosis. Findings over the past decade have not only earmarked mammalian oocyte maturation as one such case in point but have also begun to reveal a complex pattern of APC/C regulation that underpins many of the oocyte’s unique developmental attributes. This review will encompass the latest findings pertinent to the APC/C, especially APC/CCdh1, in mammalian oocytes and how its activity and substrates shape the stop–start tempo of female mammalian first meiotic division and the challenging requirement for assembling spindles in the absence of centrosomes. Reproduction (2013) 146 R61–R71 Introduction associated somatic follicular compartment at the time of ovulation. Significantly, although primordial germ cells Meiosis is the unique cell division that halves the in the ovary commit to meiosis during fetal life, it is chromosome compliment by coupling two successive not until postnatal adulthood that mature oocytes (or nuclear divisions with a single round of DNA replication. eggs) with the capacity to support fertilisation and In mammalian oocytes, this process is further compli- embryogenesis are produced, a period lasting up to cated by being drawn out over unusually protracted four to five decades in women. Intriguingly, the ovulated periods that are punctuated by two arrest stages. Following recombination between homologous egg has not yet halved its chromosome compliment as chromosomes during fetal life, oocytes arrest at the the second meiotic chromosome segregation will dictyate stage of prophase of the first meiotic division ordinarily only occur following fertilisation-induced (meiosis I or MI) until postnatal life. Following an breakage of CSF arrest. extended growth phase, hormonal cues that lead to A striking feature of human reproduction is the ovulation induce oocytes to resume and complete MI. exponential deterioration in fertility and pregnancy Resumption of MI is marked by breakdown of the success associated with female ageing (Homer 2007), membrane of the oocyte’s large nucleus, referred to as which in turn has been linked with declining oocyte germinal vesicle breakdown (GVBD), following which quality. While the oocyte’s developmental program recombined homologous chromosomes (termed biva- provides a biologically plausible explanation for this lents) are segregated (so-called homologue disjunction) phenomenon – oocytes ovulated later in life would have between the secondary oocyte and the first polar body been subjected to greater ‘ageing effects’ than oocytes (PB). Notably, MI – the interval commencing with ovulated in earlier years – exactly what the key homologous chromosome recombination and ending molecular players might be that succumb to the ageing with first PB extrusion (PBE) – in mammalian oocytes process remain to be elucidated. Before being able to incorporates one of the longest M-phases of any known identify any such pivotal regulatory nodes, it is first cell type (lasting 7–11 h in mice and 24–36 h in humans important to develop a detailed understanding of how vs tens of minutes for mitosis). Following PBE, oocytes the oocyte, in conjunction with its follicular investment, progress uninterruptedly to metaphase of the second orchestrates maturation at the molecular level. meiotic division (meiosis II or MII) and become arrested Over the past decade, increasing insight has been for a second time under the influence of cytostatic factor gained into the role that the master regulator known as (CSF). It is the CSF-arrested egg that is released from its the anaphase-promoting complex or cyclosome (APC/C) q 2013 Society for Reproduction and Fertility DOI: 10.1530/REP-13-0163 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 09/24/2021 06:26:06PM via free access R62 H Homer plays during meiotic maturation in mammalian handing over the baton to APC/CCdh1 to complete oocytes, most notably the mouse model. The APC/C proteolysis in the lead up to exit from M-phase. In has been found to be involved in virtually every mammalian oocytes, APC/CCdh1 is active at an earlier stage of mammalian oocyte development including stage than in mitosis, during prophase I arrest (equivalent G2/prophase arrest, the G2-M transition, prometaphase to late G2-phase in mitosis, hereafter G2/prophase) and I progression, the metaphase I-anaphase I transition, the prometaphase I, before APC/CCdc20 rises during late transition between MI and MII, CSF-mediated MII arrest prometaphase I to initiate homologue disjunction and calcium-related events at fertilisation. Significantly, (Homer 2011). Thus, APC/CCdh1 activity coincides with disordered control of either the APC/C or its substrates two unique aspects of mammalian oocyte development: is severely detrimental, in keeping with which mice a protracted G2/prophase arrest and an unusually bearing an oocyte-specific deletion of Apc2 (encoding extended prometaphase I. an APC/C subunit) exhibit major fertility defects (McGuinness et al. 2009). The APC/C therefore qualifies as a key molecular determinant of oocyte quality of APC/CCdh1 at the G2-M boundary: a delicate direct relevance to reproductive performance. The intention here is to review current understanding balancing act of how the APC/C and its substrates take the mammalian Maintenance of G2/prophase arrest requires suppression oocyte through the gears of MI with a focus on recent of the major cell cycle kinase, cyclin-dependent kinase 1 developments, most of which relate to the Cdh1- (Cdk1), a heterodimer composed of a catalytic Cdk1 activated species of APC/C (APC/CCdh1) and its control subunit and an activating accessory cyclin subunit. In of the G2-M transition and acentrosomal spindle contrast to the relatively low Cdk1 activity state of assembly during prometaphase I. I also refer to the G2/prophase arrest, the cellular processes involved in Cdc20-activated APC/C (APC/CCdc20) but do not delve entry into M-phase are mediated by Cdk1 activation. into great depth regarding its regulation by the spindle Thus, the mammalian oocyte is tasked with suppressing assembly checkpoint (SAC) as this has been the subject of Cdk1 for prolonged periods while at the same time recent excellent reviews (Homer 2011, Eichenlaub-Ritter maintaining the receptivity to activate Cdk1 in response 2012, Nagaoka et al. 2012, Sun & Kim 2012). to ovulatory hormonal cues. Cdk1 activity is determined by Cdk1’s phosphoryl- ation profile as well as the levels of its cyclin activating partner. Inhibitory Cdk1 phosphorylation important for Overview of the APC/C during mammalian oocyte G2/prophase arrest is induced by cAMP-dependent maturation protein kinase A (PKA) activity, which enhances the The APC/C is a cullin-RING finger E3 ubiquitin ligase embryonic Cdk1 inhibitory kinase, Wee1B (or Wee2), comprising 15–17 subunits (depending on the organism) and suppresses the activating Cdc25B phosphatase which, through ubiquitylation, targets key substrates for (Han et al. 2005, Pirino et al. 2009, Oh et al. 2010, destructionbythe26Sproteasome(Pines 2011). Solc et al. 2010). Structurally, the APC/C is broadly composed of two A novel aspect of APC/C regulation is the involvement sub-complexes, one that is catalytic and the other that of APC/CCdh1 in regulating G2/prophase arrest in mediates binding with pivotal WD40-containing mammalian oocytes (Reis et al. 2006). Important inputs co-activators, the two best characterised ones being have since been shown to provide opposing influences Cdc20 and Cdh1 (Cdc20 homologue 1; also known as on APC/CCdh1, altogether furnishing highly sophisticated Fizzy-related 1 of Fzr1). APC/C in conjunction with one fine-tuning of cyclin levels and hence of Cdk1 activity of its co-activators recognises substrates bearing specific that maintains GV arrest on the one hand while motifs or degrons, most of which can be divided into two facilitating re-entry into MI on the other hand. classes, D-boxes and KEN boxes, although there are rarer motifs including the O-, G-, A- and CRY boxes. Although Maintaining G2/prophase arrest through APC/CCdh1 the APC/C has been most extensively studied for its roles in regulating the mitotic cell cycle, important non- TheimportanceofAPC/CCdh1 for restraining Cdk1 mitotic functions have emerged; one such function through low-level cyclin B1 degradation was initially involves the unique transitions required for transforming demonstrated in vitro using morpholino antisense- immature mammalian oocytes into fertilisable eggs. mediated depletion of Cdh1 in fully grown oocytes A striking feature of MI in mammalian oocytes is the denuded of their surrounding follicular cells (Reis et al. sequence by which the APC/C
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