Molecular Human Reproduction, Vol.19, No.5 pp. 265– 278, 2013
Advanced Access publication on December 17, 2012 doi:10.1093/molehr/gas065
NEW RESEARCH HORIZON Review
Intracellular signalling during
female gametogenesis
A.P. Sobinoff, J.M. Sutherland, and E.A. Mclaughlin*
Priority Research Centre in Chemical Biology, School of Environmental and Life Sciences, University of Newcastle,
Callaghan NSW2308, Australia
*Correspondence address. Tel: +61-2-49215708; Fax: +61-2-4921-6308; E-mail: [email protected]
Submitted on September 18, 2012; resubmitted on December 2, 2012; accepted on December 8, 2012
abstract: Female reproductive potential is dictated by the size of the primordial follicle pool and the correct regulation of oocyte maturation and activation—events essential for production of viable offspring. Although a substantial body of work underpins our understanding
of these processes, the molecular mechanisms of follicular and oocyte development are not fully understood. This review summarizes recent
findings which have improved our conception of how folliculogenesis and oocyte competence are regulated, and discusses their implications
for assisted reproductive techniques. We highlight evidence provided by genetically modified mouse models and in vitro studies which have
refined our understanding of Pi3k/Akt and mTOR signalling in the oocyte and have discovered a role for Jak/Stat/Socs signalling in granulosa
cells during primordial follicle activation. We also appraise a novel role for the metal ion zinc in the regulation of meiosis I and meiosis II
progression through early meiosis inhibitor (Emi2) and Mos-Mapk signalling, and examine studies which expand our understanding of intracellular calcium signalling and extrinsic Plcz in stimulating oocyte activation.
Key words: primordial follicle / oocyte maturation/activation / Pi3k/Akt and mTOR signalling / zinc / Plcz
Introduction
Female reproduction is underpinned by a complex series of cellular
and molecular interactions orchestrated by autocrine, paracrine and
endocrine actions of ovarian growth factors, chemokines and hormones. In this review we explore the latest evidence illuminating the
actions of the multifaceted process of gametogenesis and fertilization
and link together the pivotal points of folliculogenesis, namely primordial follicle activation and oocyte maturation with egg activation and
the initiation of zygote development.
What are the intrinsic and
extrinsic factors which
ultimately dictate the female
fertile lifespan and reproductive
success?
The finite primordial follicle pool is the primary source of all the potential ‘eggs’ available for fertilization throughout a female’s reproductive lifespan. In order to prevent the pre-mature depletion of this
precious pool, the majority of these follicles remain in a quiescent
state with only a few primordial follicles recruited into the developing
population each menstrual cycle (Edson et al., 2009). Strict regulatory
control of multiple growth factors facilitates intra-follicular
communication between the primordial follicle oocyte and granulosa
cells, and extra-follicular communication with other developing follicles
(McLaughlin and McIver, 2009). Recent evidence provided by genetically modified mouse models and in vitro inhibitor studies exemplified
how these individual signalling molecules and molecular pathways
interact to maintain the primordial follicle reserve (Table I) (Castrillon
et al., 2003; Reddy et al., 2008, 2009; John et al., 2009; Sutherland
et al., 2012).
Two growth factors of interest are Kit ligand and leukaemia inhibitory factor (Lif). Kit ligand is expressed by developing granulosa cells in
primordial follicles, with its corresponding receptor being localized to
the oolemma membrane of the primordial follicle oocyte (Manova
et al., 1993). Kit ligand stimulates the intracellular phosphoinositide
3-kinase (Pi3k)/Akt signalling pathway in primordial oocytes to
promote follicular survival and activation (Bedell et al., 1995;
Yoshida et al., 1997; Thomas et al., 2008; John et al., 2009). Lif is
expressed in the pre-granulosa cells of the primordial follicle and is
thought to regulate primordial follicle activation through paracrine
and autocrine signalling (Nilsson et al., 2002). Lif was recently
shown to stimulate the Janus kinase (Jak)/signal transduction and transcription (Stat)/suppressor of cytokine signalling (Socs) signalling
pathway in activating granulosa cells; the only identified somatic cell
intracellular signalling pathway associated with follicular recruitment
(Sutherland et al., 2012). Indeed, these two pathways are thought
to interact with one another, with Lif signalling promoting Kit ligand
expression in cultured granulosa cells (Nilsson et al., 2002).
& The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Table I Summary of genetically modified mouse models.
Gene
Pathway
Knockout
Fertility phenotype
Reference
.............................................................................................................................................................................................
Foxo3a
Pi3k
Global KO;
Vasa-CreERT2
Premature primordial follicle activation, POF; induced
activation of primordial follicles
Castrillon et al. (2003); John et al.
(2008)
Akt1
Pi3k
Global KO
Retarded follicular development, increased oocyte apoptosis,
reduced granulosa proliferation
Brown et al. (2010)
Pdk1
Pi3k
Gdf9-Cre
Premature primordial follicle death, POF
Reddy et al. (2009)
Pten
Pi3k
Zp3-Cre; Vasa-CreERT2;
Gdf9-Cre
Normal; induced activation of primordial follicles and POF;
premature primordial follicle activation and POF
Jagarlamudi et al. (2009); John et al.
(2008); Reddy et al. (2008)
Tsc1;
Tsc2
mTOR
Gdf9-Cre
Premature primordial follicle activation, POF
Adhikari et al. (2009, 2010)
Rsp6
Pi3k/
mTOR
Gdf9-Cre
Premature primordial follicle death, POF
Reddy et al. (2009)
Amh
Tgfb
Global KO
Premature depletion of primordial follicles
Durlinger et al. (1999)
While the primordial follicle reserve is a representation of female
reproductive potential, the oocyte itself must undergo a series of maturational events in order to produce viable offspring. Ovarian oocytes
are maintained in prophase I arrest by high intra-oocyte cyclic adenosine monophosphate (cAMP) levels, and do not re-enter meiosis until
the pre-ovulatory surge of LH (Ayalon et al., 1972). Following germinal
vesicle breakdown the oocyte asymmetrically divides and progresses
into meiosis II (MII) before arresting again at metaphase II (Cooley,
1995). Zinc, a key regulator in many biological processes, has been recently shown to play a crucial role in the establishment, maintenance
and release of oocyte prophase I and MII arrest. Zinc maintains prophase I arrest by inhibiting the proto-oncogene serine/threonineprotein kinase mos (Mos)/mitogen-activated protein kinase (Mapk)
pathway, and regulates meiotic progression from prophase I to metaphase II by influencing maturation promoting factor (MPF) activity
(Bernhardt et al., 2011, 2012; Kong et al., 2012).
Ovulated oocytes remain arrested at MII and are induced to complete meiosis through a collective series of concurrent events termed
‘oocyte activation’ ultimately resulting in the formation of the totipotent zygote (Dale et al., 2010; Kashir et al., 2010). Mammalian
oocyte activation is reliant on intracellular calcium oscillations triggered
by fertilization (Swann and Su, 2008). These calcium oscillations are
induced by sperm-specific phospholipase C zeta 1 (Plcz1) stimulating
the production of inositol 1,4,5-trisphosphate (Ip3) which binds to
endoplasmic reticulum (ER) Ip3 receptors and causes repeated episodes of intracellular calcium release (Saunders et al., 2002; Berridge,
2009). These calcium oscillations have multiple downstream consequences including calcium-dependant zinc exocytosis resulting in the
resumption of MII via early meiosis inhibitor (Emi2) repression,
cyclin B1 degradation and MPF destabilization (Kim et al., 2011; Bernhardt et al., 2012).
Primordial follicle activation, oocyte maturation and oocyte activation represent three pivotal events essential to female fertility and
embryo development (Fig. 1). These highly regulated events are sensitive to perturbation due to genetic disorders and through exposure
to specific environmental toxicants, resulting in premature follicular activation, oocyte maturation arrest and oocyte activation deficiency
(Heytens et al., 2009b; Chen et al., 2010b; Sobinoff et al., 2012a).
Therefore, increasing our understanding of the physiological and
molecular mechanisms underlying these key processes in oocyte development will illuminate efforts to better diagnose and treat fertility
disorders. This review aims to discuss recent pertinent research and
the implications for assisted reproductive techniques.
Primordial follicle activation
Pi3k/Akt and mTOR signalling pathways;
what regulates these two central oocyte
specific pathways of primordial follicle
activation?
The Pi3k/Akt signalling pathway is an important regulator of cell proliferation and survivability and has been implicated in stem cell maintenance, organogenesis and primordial follicle activation (Fig. 2)
(Cantley, 2002). Attention focused on Pi3k/Akt signalling in
oocyte-induced primordial follicle activation with the identification of
the downstream transcription factor Forkhead box O3a (Foxo3a) as
a master regulator and suppressor of primordial follicle recruitment
(Castrillon et al., 2003). Oocyte-specific deletion of phosphatase
and tensin homolog (Pten), an upstream negative regulator of Pi3k signalling, resulted in Akt hyperactivation. This resulted in Foxo3a hyperphosphorylation and nuclear export, culminating in global primordial
follicle activation and premature ovarian failure (Reddy et al., 2008).
Interestingly, mice lacking both oocyte Pten and Foxo3a demonstrated
a lack of synergistic primordial follicle activation, indicating they may
work in concert to maintain primordial follicle dormancy (Reddy
et al., 2008). Pharmacological inhibition studies using the Pi3k-specific
inhibitor LY294002 also demonstrated reduced primordial follicle activation in ovaries lacking Pten in oocytes, but not in ovaries lacking
Foxo3a, suggesting Pten acts upstream of Foxo3a (Vlahos et al.,
1994; John et al., 2008). Evidence for perturbed Pi3k signalling in toxicology studies reveals an environmental mode of ovotoxicity. Both cigarette smoke constituents 9:10-dimethyl-1:2-benzanthracene (DMBA)
and 3-methylcholanthrene (3-MC) and the industrial by-product 4vinylcyclohexene diepoxide (VCD) cause premature ovarian failure
via excessive stimulation of primordial follicle recruitment in rodents
(Keating et al., 2009; Sobinoff et al., 2011, 2012b). Primordial follicle
Intracellular signalling during female gametogenesis
267
Figure 1 Diagrammatic representation of primordial follicle activation, oocyte maturation and oocyte activation. (A) The follicular activation of the
dormant primordial follicle occurs in response to cytokine growth factors (e.g. Kit and Lif) and is characterized by oocyte growth and granulosa cell
differentiation/proliferation. (B) Oocyte maturation occurs in response to the LH surge, resulting in meiotic resumption and arrest at metaphase II.
(C) Oocyte activation occurs in ovulated oocytes after fertilization, resulting in the completion of MII, extrusion of the second polar body and male/
female pro-nuclear formation. Images are not to scale.
activation was accompanied by activation of members of the Pi3k/Akt
signalling pathway in the oocytes of DMBA and 3-MC cultured ovaries,
while VCD-induced stimulation was attenuated by LY294002, further
implicating aberrant Pi3k signalling in precocious primordial follicle
activation.
Pi3k/Akt signalling induces pyruvate dehydrogenase kinase isoenzyme
1 (Pdk1)/Akt/ ribosomal protein S6 kinase polypeptide 1 (S6k1)/ribosomal protein S6 (rpS6) signalling in primordial follicle oocytes (Engelman
et al., 2006; Reddy et al., 2009). Pdk1 is a Pi3k-dependant protein
kinase which binds Pi3k-generated 3,4,5-triphosphate (Pip3) to
co-activate Akt by phosphorylating its T308 residue (Engelman et al.,
2006). Oocyte-specific deletion of Pdk1 abates excessive primordial follicle activation seen in Pten null ovaries (Reddy et al., 2009) and activated
Akt and Foxo3a are reduced in Pdk1-deficient oocytes. Since depressed
pAKT and Foxo3a were not restored by Pi3k stimulation, Pdk1 is likely to
be essential for primordial follicle activation (Reddy et al., 2009).
Pdk1 also plays an essential role in phosphorylating and activating
S6k1, a serine/threonine-protein kinase which in turn phospho-activates the 40S ribosomal protein, rpS6, stimulating protein translation
and ribosome biogenesis during cell growth (Pullen et al., 1998;
Ruvinsky and Meyuhas, 2006). S6k1 and rpS6 activation were shown
to be up-regulated in Pten-deficient oocytes, and were reduced with
the concurrent abolition of Pdk1. In addition, Pi3k stimulation in
Pdk1-deficient oocytes did not restore S6k1 activity, while phosphorylation levels of rpS6 were significantly down-regulated in the oocyte
(Reddy et al., 2009). Combined, these results indicate that rpS6 in
oocytes is important in maintaining the survival of primordial and
developing follicles.
S6k1 also acts downstream of a converging pathway, the mechanistic target of rapamycin (mTOR) signalling cascade. A key component of this pathway, mTORC1, is a serine/threonine kinase
[complex containing mTOR, Raptor, target of rapamycin complex
subunit Lst8 (mLst8/Gbl), proline-rich protein (Pras40) and DEP
domain containing MTOR-interacting protein subunits] promotes
cell proliferation, cell growth and cell cycle progression in response
to growth factors and nutrient status (Wullschleger et al., 2006).
In mammalian cells, mTORC1 activity is phospho-regulated by a heterodimeric complex consisting of two protein molecules: tuberous
sclerosis protein 1 (Tsc1) and tuberous sclerosis protein 2 (Tsc2)
(Cheng et al., 2004; de Vries et al., 2007). This complex suppresses
the activation of mTORC1 via a GTPase-activating protein domain in
Tsc2, which stimulates Ras homolog enriched in the brain (Rheb)
GPTase activity and prevents its stimulatory effect on mTOR signalling. The role of Tsc1 in the complex is to protect Tsc2 from ubiquination and degradation (Chong-Kopera et al., 2006).
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Sobinoff et al.
Figure 2 Diagrammatic representation of primordial follicle phosphatidylinositol-3 kinase/protein kinase B (Pi3k/Akt) and mTOR(target of rapamycin) signalling. Rtk (receptor tyrosine kinase) activation by growth factors results in Pi3k activation, which subsequently facilitates the conversion of
membrane-bound phosphatidylinositol (3,4,5)-bisphosphate (Pip2) to phosphatidylinositol (3,4,5)-trisphosphate(Pip3) via phosphorylation, an event
reversed by phosphatase and tensin homolog (Pten). Membrane-bound Pip3 provides a docking site for 3-phosphoinositide-dependent protein
kinase-1 (Pdk1) and Akt1, resulting in Pdk1-induced Akt1 phosphorylation. Akt1 then crosses the nuclear membrane and phosphorylates Foxo3a
transcription factor, resulting in its translocation from the nucleus to the cytoplasm, stimulating follicular activation. Tuberous sclerosis protein 1
(Tsc1/Tsc2) complex repression via an unknown mechanism allows mTORC1 phospho-activation. Akt1, Pdk1 and mTORC1 then enhance
S6k1-rpS6 signalling through S6k1 phosphorylation, stimulating protein translation and ribosome biogenesis.
Tsc2 is phosphorylated on its S939 residue by pAkt1 as part of the
Pi3k/Akt signalling cascade, resulting in its sequestration from Tsc1 by
14-3-3 proteins to allow mTOR activation (Cai et al., 2006). Stimulation of Pi3k signalling in primordial follicle oocytes invokes Aktmediated Tsc2 phosphorylation (Adhikari et al., 2009). In support of
the intimate involvement of mTOR signalling, primordial follicles deficient in oocyte Tsc1 are recruited into the developing pool prematurely due to enhanced mTORC1 activation of S6k1 via T389
phosphorylation, followed by downstream rpS6 S235/6 phosphorylation and eIF4B expression (Adhikari et al., 2010). Rapamycin, an
mTORC1 specific inhibitor, was able to reverse these effects in
Tsc1-deficient mice, confirming that mTORC1 dysregulation accelerated follicle activation (Kim et al., 2002; Adhikari et al., 2010).
Although Tsc2 regulation of mTOR signalling can occur downstream of Pi3k/Akt signalling, this is not the case in primordial follicle
activation. Oocyte-specific abolition of Pten results in increased Akt
activation followed by Foxo3a inhibition and S6k1 T229 phosphorylation (Reddy et al., 2009). However, Tsc1 deletion causes
mTORC1 activation followed by the alternate S6k1 phosphorylation
on residue T389 (Adhikari et al., 2010). Concomitant oocyte-specific
abolition of Pten and Tsc1 results in a greater level of premature
activation (Adhikari et al., 2010). Therefore, Pi3k/Akt and mTOR signalling work synergistically to promote primordial follicle activation
through a unique combination of intracellular signalling mechanisms
in the oocyte. Intriguingly, these results suggested that these pathways
are directed via different ligands, and support the notion that primordial follicle activation is subject to multiple paracrine and autocrine
direction.
Kit ligand and Pi3k/Akt signalling; regulators
of primordial follicle activation or survival?
Unlike the later stages of follicular development primordial follicle activation appears to be gonadotrophin independent, suggesting its regulation is reliant on intrafollicular signalling between the oocyte and
granulosa cells (McLaughlin and McIver, 2009). Therefore, Pi3k/Aktmediated primordial follicle activation is directly controlled by locally
released cytokines and growth factors. A potential regulator of
Pi3k/Akt signalling in primordial follicles is Kit Ligand (Kitl) and its
cognate receptor tyrosine kinase Kit which play numerous roles
during germ cell development including primordial germ cell survival,
proliferation, migration and differentiation (Bedell and Zama, 2004).
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Intracellular signalling during female gametogenesis
Kitl signals through multiple pathways, including Pi3k/Akt (Serve et al.,
1994; Blume-Jensen et al., 2000; Kissel et al., 2000). Kitl is also
expressed by developing granulosa cells, while its receptor is located
on the oocyte plasma membrane (Manova et al., 1993). While
certain alleles of murine Kitl (also known as the Steel locus) show
reduced levels of primordial follicle activation and arrested follicular
maturation (Huang et al., 1993; Bedell et al., 1995), direct evidence
for the action of Kitl in follicle activation is limited. For example,
antibody-mediated blockade of Kit has been shown to disrupt primordial follicle activation in vitro and in vivo, while the addition of recombinant Kitl to ovaries in culture induces primordial follicle activation
(Packer et al., 1994; Yoshida et al., 1997; Thomas et al., 2008). Addition of recombinant Kitl to isolated oocytes has also been shown to
induce Pi3k/Akt and mTOR signalling, as evidenced by Akt activation,
Foxo3a phospho-inhibition and Tsc2 phospho-inhibition (Reddy et al.,
2009).
Although the aforementioned studies build a strong case for Kitldirected primordial follicle activation, recent analysis of a knock-in
allele of the Kit receptor (KitY719F) refutes this idea. The KitY719F
allele completely abrogates Kit signalling via Pi3k by mutating Tyrosine
residue 719 of the Kit receptor, preventing autophosphorylation following ligand binding (Serve et al., 1994). Mice homozygous for this
allele did not show any abnormal signs of primordial follicle activation,
and have normal fertility at 16 weeks of age, suggesting Kit signalling via
Pi3k is entirely dispensable for this process (John et al., 2009).
However, other abnormalities were present in homozygous KitY719F
ovaries, such as accelerated primordial follicle death, and the accumulation of morphologically abnormal follicles arrested at the primary follicle stage. A re-evaluation of the Steel allele of Kitl also demonstrated
folliculogenesis was arrested at the primary follicle stage, and may be
due to the observed increase in Foxo3a nuclear retention which has
been previously associated with primary follicle arrest (Liu et al.,
2007; John et al., 2009). Therefore, Kitl may not play a role in the initiation of primordial follicle activation but almost certainly plays a role
in follicular progression via Pi3k/Akt signalling.
As described previously, homozygous KitY719F ovaries demonstrated increased signs of accelerated primordial follicle death in addition to arrested development (John et al., 2009). Thus, Kitl may play a
role in maintaining the primordial follicle pool by preventing premature
follicular atresia via Pi3k/Akt signalling (Sullivan and Castrillon, 2011).
Indeed the Pi3k/Akt signalling pathway, a major regulator of cell survival, has recently been implicated in increased primordial follicle survivability in response to ovotoxic insult (Sobinoff et al., 2012b). In
cultured rodent ovaries, primordial follicle depletion caused by the
ovotoxicant VCD was shown to be attenuated through the addition
of Kitl, suggesting the growth factor was increasing primordial follicle
oocyte survivability (Fernandez et al., 2008). Furthermore, exposure
of cultured neonatal ovaries to VCD resulted in decreased levels of
Kit receptor autophosphorylation and Akt activation in cultured
ovarian explants (Keating et al., 2011). Therefore, this autophosphorylation of the Kit receptor, and Pi3k/Akt activation suggests that VCD
induced primordial follicle activation may be due to inhibition of Kitl
signalling. VCD may interfere directly with the Kit receptor to
reduce Kitl signalling as co-incubation of neonatal ovaries with VCD
and a non-function blocking anti-mouse Kit4 antibody resulted in
the partial restoration of Kit receptor autophosphorylation (MarkKappeler et al., 2011). Also, Pi3k/Akt signalling may preserve the
primordial follicle pool by stimulating pro-survival events, such as the
phospho-inhibition of Bcl-2-associated death promoter (Bad) in the
presence of the ovotoxicant 3MC (Sobinoff et al., 2012b). Combined,
these ovarian toxicology studies provide support for Kitl and its Pi3k/
Akt signalling pathway in promoting primordial follicle survival, but not
as a necessary requirement for primordial follicle activation. In
summary the search for the elusive growth factor/cytokine responsible for primordial follicle activation continues.
Lif and the Jak/Stat/Socs signalling: a
regulator of pregranulosa cell follicular
recruitment?
Lif is a pleiotropic cytokine linked to cell proliferation and stem cell
maintenance (Williams et al., 1988; Gearing et al., 1991). Mechanistically, Lif binds to its heterodimer receptor to stimulate the Jak/Stat/
Socs signalling pathway (Heinrich et al., 1998; Rawlings et al., 2004)
(Fig. 2). Jak activation occurs following Lif receptor multimerization
and Jak trans-phosphorylation (Taga and Kishimoto, 1997). Activated
Jak phospho-activates Stat family members causing dimerization and
nuclear translocation via the Ran nuclear import pathway. Nuclear
Stats bind specific regulatory sequences to activate or repress transcription of target genes and is ultimately regulated by a negative feedback loop through Socs signalling (Rawlings et al., 2004). Socs proteins
can inhibit Jak/Stat signalling by binding directly to the phosphorylated
Jak, Jak receptors or Stats, blocking kinase activity and preventing Stat
binding and dimerization (Croker et al., 2008).
Early ovarian studies identified Lif expression in the granulosa cells
of primordial and later stage follicles, with co-culture of the cytokine
and ovarian explants stimulating primordial follicle activation (Nilsson
et al., 2002). Later studies revealed that Jak1, Stat3 and Socs4 were
up-regulated in association with the morphological changes associated
with pre-granulosa cell activation (Holt et al., 2006). Recently, Sutherland et al. (2012) identified a role for Lif-mediated Jak1/Stat3/Socs4
signalling in pre-granulosa cell activation during follicular recruitment
(Fig. 3). Lif induced primordial follicle activation and increased total
Stat3 protein in primordial and activating follicle oocytes (Sutherland
et al., 2012). However, increased phospho-activated Stat3 was
detected in the granulosa cell nucleus of activating follicles but not in
the oocyte. This indicates granulosa cell-specific Stat signalling. Socs4
was also up-regulated in Lif-stimulated activating and primary follicle
granulosa cells, presumably influenced by increased Stat3 signalling
(Sutherland et al., 2012). These results suggest a novel ovarian follicular pathway in which Lif promotes Stat3 activation in recruited follicle
granulosa cells, ultimately up-regulating Stat responsive Socs4.
How does Stat3 activated transcription
influence granulosa cell proliferation and
differentiation?
Sutherland et al. also identified novel interactions between
Poly(rC)-binding protein 1 (Pcbp1), malate dehydrogenase 1 (Mdh1)
and cardiotrophin-like cytokine (Clc) as binding partners of Socs4 in
the ovary via protein –protein pulldowns (Sutherland et al., 2012).
Pcbp1, an RNA-binding protein with known associations with Stat3,
was shown to be expressed in the oocyte and granulosa cells of
growing follicles, and was increased in Lif-treated ovaries (Nishinakamura et al., 2007). Depletion of Stat3 via RNAi knockdowns in
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Sobinoff et al.
Figure 3 Diagrammatic representation of hypothesized Jak1/Stat3/Socs4 signalling in mammalian granulosa cells. LIF binding to its receptor
complex causes the cross phosphorylation of associated Jak1, which in turn causes the phosphorylation of the receptor complex, enabling Stat3
binding and phospho-activation. Phosphorylated Stat3 then form dimers and are transported within the nucleus and binds to specific regulatory
sequences to activate Socs4 expression. Socs4 acts as a negative regulator of Jak/Stat signalling by binding phosphorylated Jak1 and its receptor to
prevent the activation of Stat3. Socs4 has also been shown to bind cardiotrophin-like cytokine (Clc), malate dehydrogenase 1 (Mdh1) and
poly(rC)-binding protein 1 (Pcpb1), possibly regulating their functions.
primary granulosa cell culture caused a decrease in Pcbp1 mRNA expression, suggesting it is Stat3 responsive (Sutherland et al., 2012). In
contrast, Socs4 RNAi knockdowns resulted in a non-significant observable decrease. These results suggest Pcbp1 expression is regulated by
Stat3 in response to Lif; its interaction with Socs4 being a negative repressor of activation. Mdh1, a mitochondrial protein that plays a role
in the citric acid cycle, was also expressed in the oocyte and granulosa
cells of growing follicles, increased by Lif in cultured ovaries, and transcriptionally reduced in primary granulosa Stat3 RNAi knockdowns
(Yoon et al., 2006; Sutherland et al., 2012). Socs4 may bind Mdh1 to
regulate metabolic responses in granulosa cells from the mitochondria
via similar mechanisms to mitochondrial Stat3 (Wegrzyn et al., 2009;
Phillips et al., 2010). Clc is an interleukin-6 cytokine that binds to the
same receptor as Lif, resulting in the induction of similar signalling cascades (Heinrich et al., 2003; Katoh, 2007). Clc expression was localized
to the granulosa and theca cells during all stages of pre-antral follicular
development, and was increased with Lif exposure in cultured ovaries
(Sutherland et al., 2012). Therefore, Clc may contribute to primordial
follicle activation, interacting with Socs4 in a negative feedback loop
(Heinrich et al., 2003; Katoh, 2007; Croker et al., 2008). The importance
of the Jak/Stat/Socs signalling pathways is well documented in gametogenesis in lower organisms such as Drosophilia (Lopez-Onieva et al.,
2008). However, the role of this pathway in mammalian folliculogenesis
remains relatively uncharacterized and may underpin molecular-based
therapeutics for the control of follicle activation and development.
Oocyte maturation
Zinc: an unexpected promoter of oocyte
maturation?
The metal ion zinc is an integral component of many metalloproteins
and an essential component of many biological processes (Maret,
2001). Recently, evidence identifying zinc as a potential intracellular
secondary messenger in cell-to-cell signalling has emerged (Yamasaki
et al., 2007). In reproduction, zinc is important for several aspects
of male fertility including testis development and capacitation
(Hamdi et al., 1997; de Lamirande et al., 2009). While zinc deficiency
has also been linked with adverse pregnancy outcomes and abnormal
ovulation, its role in oocyte development has only recently been
reported (Ebisch et al., 2007; Kim et al., 2010; Bernhardt et al.,
2011; Kong et al., 2012). A recent study indicates that proper zinc
homeostasis is also required for the maintenance of prophase I
arrest in oocytes through the Mos/Mapk pathway (Kong et al.,
2012). Disrupting zinc availability in prophase I arrested oocytes
using the heavy metal chelator N, N, N′ ,N′ -tetrakis-(2-
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Intracellular signalling during female gametogenesis
pyridylmethyl)-ethylenediamine (TPEN) causes pre-mature meiotic
resumption that is not reversed in the presence of the phosphodiesterase inhibitor milrinone (Wiersma et al., 1998; Taki et al.,
2004; Kong et al., 2012). Interestingly, TPEN-induced meiotic resumption also coincides with the premature activation of the Mos/Mapk
pathway (Kong et al., 2012). Precocious activation of the Mos/Mapk
pathway causes premature meiotic resumption in the presence of
the phosphodiesterase inhibitor milrinone, mimicking zinc insufficiency
(Choi et al., 1996). This collectively suggests that zinc may maintain
prophase I arrest through inhibiting the Mos/Mapk pathway. Indeed,
inhibition of Mos translation using siRNA significantly decreased
TPEN’s ability to cause premature meiotic resumption, while the addition of the global translational silencer cycloheximide completely
abrogates TPEN-induced pre-mature meiotic resumption (Kong
et al., 2012). Combined, these results support a mechanism of
zinc-induced prophase I arrest via the inhibition of Mos translation,
thereby silencing the Mos/Mapk pathway through a currently undescribed mechanism.
It has been postulated that these oscillations are of physiological
relevance as the total zinc content of maturing oocytes undergoes
large fluxes during the first round of meiotic resumption (Kim et al.,
2010). Limiting zinc up-take during the first round of in vitro maturation
(IVM) using TPEN results in the symmetrical division of the polar body
and arrest at telophase I (Kim et al., 2010). The incorrect asymmetrical
division in zinc-deficient oocytes during meiosis I was found to be
associated with aberrant cortical granule organization and a subsequent failure to form a cortical granule-free domain, which could be
related to failed cellular polarization (Bernhardt et al., 2011). MPF, a
heterodimer consisting of cyclin-dependent kinase 1 and cyclin B1,
regulates meiotic resumption through phosphorylation events that initiate germinal vesicle breakdown (Josefsberg et al., 2003). Telophase I
arrest in zinc-deprived oocytes was due to insufficient MPF activity due
to a failure to re-accumulate cyclin B1 after metaphase I (Bernhardt
et al., 2011). These oocytes can be rescued from telophase I arrest
by the expression of non-degradable cyclin B1 (Bernhardt et al.,
2011). MPF formation is dependent on the activity of early meiosis inhibitor 2 (Emi2), which prevents cyclin B1 degradation by inhibiting the
anaphase-promoting complex and has been suggested as a possible
target for zinc-regulated meiosis I to meiosis II progression (Bernhardt
et al., 2011). Recent evidence has shown that a functional Emi2-zinc
binding region contributes to the ability of Emi2 to artificially arrest
oocytes at metaphase I (Suzuki et al., 2010a). Indeed, meiotic arrest
induced by Emi2 cRNA injection into prophase I oocytes is partially
reversed with the addition of TPEN, demonstrating a requirement
for zinc in Emi2-mediated prophase I arrest (Bernhardt et al., 2012).
Additionally, rescuing zinc-deficient oocytes arrested at telophase I
with exogenous zinc supplementation resulted in symmetrical division,
suggesting a possible role for zinc in determining oocyte versus polar
body cell fate (Kim et al., 2010).
Recently, Tian and Diaz (2012) also demonstrated a requirement
for zinc in maintaining prophase I arrest and correct meiotic progression in vivo. Oocytes from mice fed on a zinc-deficient diet for 10 days
exhibited pre-mature maturation of 42.5% of collected deficient
oocytes (Tian and Diaz, 2012). Confocal immunofluorescence demonstrated these oocytes also had abnormal spindle configurations, and
were arrested at both metaphase and telophase I (Tian and Diaz,
2012). These results were similar to those observed in TPEN-treated
oocytes, and confirm zinc as an essential factor for maintaining prophase I arrest and meiosis I completion in vivo (Kim et al., 2010; Bernhardt et al., 2011, 2012; Kong et al., 2012). In addition to the 10-day
treated animals, mice fed on a zinc-deficient diet for 3 days also
resulted in a failure to complete meiosis I with the absence of a
polar body in 23% of ovulated oocytes (Tian and Diaz, 2012). In
summary, the acute nature (3 –10 days zinc insufficiency) of these in
vivo experiments highlights the critical importance of zinc in the regulation of oocyte meiosis.
Given no other cell type reportedly utilizes zinc in such a unique
way, the identification of zinc as a novel regulator of prophase I
arrest and correct meiotic progression through oocyte maturation is
particularly intriguing (Kim et al., 2010). As the oocyte remains transcriptionally quiescent during final maturation, the identification of inorganic zinc as a potential secondary messenger may provide the
‘missing link’ in the regulation of meiotic progression.
Oocyte activation
Calcium, zinc and Plcz1: three
complementary master regulators of
oocyte activation?
Oocyte activation occurs directly after fertilization, and involves morphological and biochemical events resulting in the resumption and progression of MII and entry into embryogenesis (Dale et al., 2010; Kashir
et al., 2010). Cortical granule exocytosis preventing polyspermy, extrusion of the second polar body, maternal RNA recruitment and
male and female pro-nuclear formation are essential events in
zygote formation. A concomitant series of cytosolic calcium oscillations are now thought to be the universal trigger for oocyte activation,
with calcium microinjection alone initiating zygote development to the
blastocyst stage (Fulton and Whittingham, 1978; Miyazaki and Ito,
2006). Calcium oscillations are important for both early and late
stage oocyte activation (Fissore et al., 1992; Kline and Kline, 1992).
Early oocyte activation is not initiated immediately following an initial
increase in intracellular calcium, instead occurring in a temporal
order following the periodic accumulation of intracellular calcium to
ensure optimal developmental competence (Lawrence et al., 1998;
Ozil et al., 2005; Boulware and Marchant, 2008). For example,
calcium oscillations caused by either fertilization or parthenogenesis
initiate calcium-dependant zinc exocytosis; a series of events termed
‘zinc sparks’ which have been hypothesized to allow MII oocytes to
enter meiotic resumption (Kim et al., 2011). Meiotic resumption can
be triggered artificially using TPEN, and inhibited by overloading the
oocyte with zinc ionophores (Suzuki et al., 2010b; Bernhardt et al.,
2012). Indeed, TPEN treatment was shown to be sufficient to activate
MII-arrested oocytes injected with ‘inactivated’ sperm heads in the
absence of intracellular calcium oscillations, resulting in live births
after embryo transfer (Suzuki et al., 2010b). In addition to confirming
a critical role for zinc in meiotic resumption, these results also imply
that the sole indispensable role of fertilization-induced calcium
release is MII exit. Like prophase I arrest, zinc has also been shown
to regulate MII meiotic progression through interactions with Emi2.
In a recent study, prophase I-arrested oocytes injected with a Emi2
morpholino targeted against a sequence specific to the Emi2 5′ untranslated region underwent premature meiotic progression and
272
failed to arrest at MII (Bernhardt et al., 2012). Introducing wild-type
Emi2 cRNA to these Emi2-deficient oocytes after polar body formation restored MII arrest in 73% of oocytes (Bernhardt et al., 2012).
However, introducing mutant Emi2 cRNA with a single amino acid
substitution in the zinc-binding region only restored MII arrest in
41% of oocytes, suggesting Emi2 function is dependant on zinc
binding (Bernhardt et al., 2012). Therefore, calcium-dependant zinc
exocytosis may be responsible for Emi2 repression, resulting in
cyclin B1 degradation and MPF destabilization, thereby alleviating MII
arrest.
Calmodulin-dependent protein kinase II gamma (CamkIIg) is
another transducer of the calcium signal required for meiotic resumption following fertilization (Chang et al., 2009; Backs et al., 2010).
CamkIIg activity is stimulated after fertilization with CamkIIg insufficient oocytes failing to re-enter meiosis despite exhibiting correct
calcium oscillations and cortical granule exocytosis (Chang et al.,
2009; Backs et al., 2010). As MII oocytes can be parthenogenetically
activated with a constitutively active form of CamkIIg without
calcium, CamkIIg appears to be downstream of calcium oscillations
(Backs et al., 2010). Additionally, female CamkIIg knockout mice are
sterile due to a failure to reduce MAPK and Cyclin-dependant
kinase 1 (Cdk1)/cyclin B levels and allow meiotic resumption (Backs
et al., 2010). In Xenopus oocytes, xCaMKII causes cyclin B repression
by targeting xEmi2 for destruction (Hansen et al., 2006). However,
Suzuki et al. (2010a) found that the two isoforms of CamkIIg found
in mammalian oocytes do not phosphorylate Emi2 in vitro.
Calcium oscillations may also target the mitochondria at fertilization.
Calcium oscillations in fertilizing mouse oocytes coincide with oscillatory increases in the reduction of enzymes flavin adenine dinucleotide
and nicotinamide adenine dinucleotide (Dumollard et al., 2004). It has
been hypothesized that calcium increases in the cytosol result in a concurrent increase in mitochondrial matrix calcium, activating mitochondrial dehydrogenases (Pozzan and Rizzuto, 2000). This hypothesis is
supported by transient increases in ATP levels following fertilization
(Campbell and Swann, 2006).
Calcium oscillations in mammalian oocytes are caused by inositol
triphosphate (Ip3) mediated calcium release from intracellular stores
such as the ER (Swann and Su, 2008). This elevated calcium is subsequently sequestered via the reuptake into the ER or by extracellular
expulsion. Blocking or down-regulating the expression of Ip3 receptors
in both mouse and hamster oocytes inhibit calcium oscillations, and
therefore oocyte activation (Miyazaki, 1992; Jellerette et al., 2000;
Xu et al., 2003). Cytosolic increases in Ip3 during fertilization and
the inability of other calcium-releasing agents to stimulate calcium
oscillations in mouse oocytes provide further support for a unique
model of Ip3-mediated intracellular calcium release (Shirakawa et al.,
2006; Swann and Su, 2008). As calcium oscillations immediately
follow after fertilization, they must be mediated by the male gamete
(Cuthbertson and Cobbold, 1985). The success of ICSI as a method
of IVF suggests that this event is not regulated by a sperm ligand/
oocyte receptor model. As this technique bypasses sperm/oocyte receptor binding by injecting spermatozoa directly into the oocyte cytoplasm, it was hypothesized that sperm release a soluble oocyte
activation factor after fertilization, and the search for an Ip3 activator
began (Jones et al., 1998; Rice et al., 2000).
Following extensive experimentation, the testis-specific enzyme
phospholipase C Plcz, is now thought to be this oocyte activation
Sobinoff et al.
factor (Saunders et al., 2002) (Fig. 4). Plcz is the smallest mammalian
Plc with a mass of 70 kDa, and consists of four EF hand domains that
bind calcium, a C2 domain, a X and Y catalytic domain found in all
mammalian Plcs and an absent PH domain (Rebecchi and Pentyala,
2000). Microinjection of both Plcz cRNA and recombinant protein
into mouse oocytes triggers calcium oscillations similar to those
seen after fertilization (Saunders et al., 2002; Kouchi et al., 2004).
PLCz is also predominantly localized to the equatorial, acrosomal
and post-acrosomal regions of human sperm, suggesting rapid access
to the ooplasm following sperm –oocyte fusion (Manandhar and
Toshimori, 2003; Sutovsky et al., 2003; Grasa et al., 2008). The
level of sperm-derived Plcz is also sufficient to trigger calcium oscillations in the mouse oocyte (Saunders et al., 2002). Furthermore, depletion of Plcz from transgenic sperm using RNAi impairs intracellular
calcium oscillations after fertilization, reducing both the amplitude
and duration of the first calcium transient and reducing the persistence
of subsequent calcium oscillations (Knott et al., 2005). Human studies
have shown injection of human Plcz cRNA into human oocytes also
initiates calcium oscillations leading to preimplantation development
(Rogers et al., 2004; Yoon et al., 2012). Sperm from a population of
infertile men which consistently fail to induce correct calcium oscillations after IVF or ICSI also have absent, abnormal isoforms or
reduced levels of PLCz (Heytens et al., 2009a; Kashir et al., 2012a, b).
According to the current model of Plcz-mediated oocyte activation,
Plcz is released into the cytoplasm of the mammalian oocyte after
gamete fusion where it facilitates the hydrolysis of phosphatidylinositol
4,5-bisphosphate (Pip2) into Ip3, triggering intracellular calcium oscillations and resulting in oocyte activation (Fig. 3) (Saunders et al., 2007).
Although other Plc isoforms target oolemma membrane-bound Pip2,
evidence suggests Plcz targets intracellular membrane-bound Pip2 on
distinct vesicular structures within the mouse oocyte cortex (Yu et al.,
2012). Recombinant human PLCz also localizes to regions near the
nuclear envelope in HEK293T cells, and fails to induce calcium oscillations in the CHO cell line which are devoid of organelle-bound Pip2,
suggesting PLCz may target organelle-bound Pip2 (Kashir et al., 2011;
Phillips et al., 2011). In the mouse, Plcz translocates from the cytoplasm to the pro-nucleus during the zygotic interphase of the first
cell cycle, restricting its access to membrane-bound Pip2 and terminating calcium oscillations after fertilization (Ito et al., 2008).
In addition to controlling calcium signalling during oocyte activation,
Plcz may also act to stimulate protein kinases involved in oocyte activation. Mammalian oocytes contain a number of different protein
kinase C (Pkc) isoforms stimulated by both calcium and diacylglycerol
(Halet, 2004). Plcz produces diacylglycerol and Ip3 when it enters the
oocyte, both of which are known to act in concert to stimulate Pkc
activity (Tatone et al., 2003). Indeed, Pkc activity has been shown
to increase after fertilization, with different isoforms translocating to
either the plasma membrane or meiotic spindle (Tatone et al.,
2003; Page Baluch et al., 2004).
Although there is a substantial body of evidence to suggest Plcz is a
sperm-borne oocyte activation factor, a recent study performed by
Aarabi et al. contests that Plcz is compartmentalized in the acrosomal
and post-acrosomal regions of multiple species, and was not present
on boar sperm heads during sperm-oolemma binding and incorporation into the oocyte (Aarabi et al., 2012). Overall, this study contends
that both Plcz localization and absence during gamete fusion is not
consistent with that of a sperm-borne oocyte activating factor.
273
Intracellular signalling during female gametogenesis
Figure 4 Diagrammatic representation of phospholipase C (Plc)z-mediated oocyte activation. Spermatozoa bound Plcz is released into the oocyte
cytoplasm during fertilization, where it subsequently facilitates the conversion of organelle bound Pip2 into inositol triphosphate (Ip3) and diacylglycerol
(DAG). Ip3 then interacts with receptors of the ER, resulting in the movement of calcium to and from the ER and the extra-cellular space. These
calcium oscillations stimulate a number of events including co-activation of protein kinase C (Pkc) with DAG, increased mitochondrial calcium concentrations stimulating energy production and early meiosis inhibitor (Emi2) repression through zinc co-factor exocytosis and calcium-dependant
protein kinase (CamkII)g activation resulting in MPF degradation.
These results conflict with previous reports of Plcz localization, highlighting the need for future studies in numerous species before an
overall consensus can be reached (Yoon and Fissore, 2007; Grasa
et al., 2008; Kaewmala et al., 2012).
Recent evidence has suggested that calcium influx across the oocyte
plasma membrane during fertilization is also required for oocyte activation (Miao et al., 2012). Although calcium is sequestered back into
the ER during each calcium oscillation, a proportion of the intracellular
reserves are lost by the oocyte expunging calcium from the cell. The
oocyte regains some of this lost calcium through calcium influx to replenish its intracellular stores (Igusa and Miyazaki, 1983; Kline and
Kline, 1992). Interestingly, the absence of calcium influx after fertilization resulted in the failure of the oocyte to extrude the second polar
body and the formation of three pro-nuclei. Experiments using the
calcium chelator BAPTA/AM also demonstrated that fertilized
oocytes cultured in a calcium-free medium remained arrested at metaphase II (Miao et al., 2012). Calcium influx also appears to occur upstream of CamkIIg activation, as oocytes can be parthenogenetically
activated by constitutively active recombinant CamkIIg in the
absence of extracellular calcium (Miao et al., 2012). In summary
these results suggest that the cytoplasmic calcium oscillations alone
may not be sufficient for oocyte activation, and that a secondary
calcium influx is required to activate downstream calcium signalling
molecules.
Conclusions
The studies described in this review have greatly contributed to our
understanding of primordial follicle activation and oocyte maturation/activation. Although further work is required to completely elucidate the mechanisms behind these processes, there are already a
number of clinical applications for this knowledge. Ovarian failure is
a major side effect for women undergoing certain cytotoxic chemotherapy and/or radiotherapy (Jeruss and Woodruff, 2009). Embryo
cryopreservation represents the standard treatment for those
women who wish to conceive following therapy (West et al., 2009;
Noyes et al., 2011). Unfortunately, the extensive hormonal treatment
required for ovarian stimulation may not be optional for women with
aggressive malignancies, and may cause high serum concentrations of
estrogen which could promote the growth of hormone-sensitive
tumours (Subramanian et al., 2008). Furthermore, embryo storage is
274
not an option for patients with pre-pubertal cancer or those without
long-term partners (Lobo, 2005).
A potential solution to these problems is the still experimental cryopreservation of primordial follicle-rich ovarian cortical tissue, and the
development of fertilizable ova through in vitro follicular activation
(Lee et al., 2006; Jeruss and Woodruff, 2009; Noyes et al., 2011).
Our increased knowledge of primordial follicle activation could aid
in perfecting this technique. For example, culturing ovarian sections
in the presence of Pi3k/Akt, mTOR or Jak/Stat inhibitors or activators
could trigger primordial follicle activation in vitro. Indeed, Adhikari et al.
(2012) have recently used the Pten inhibitor bpV(HOpic) to successfully activate primordial follicles from neonatal mouse ovaries which
were then transplanted under the kidney capsules of recipient mice
to generate mature oocytes. These oocytes were subsequently fertilized in vitro and used to generate progeny after embryo transfer. Crucially, as human follicular development takes several weeks in vivo, a
suitable culturing method must first be developed before these techniques can be translated into the clinic (Gougeon, 2010).
Although recent studies have found an essential role for zinc in the
regulation of meiosis I and MII in rodents, relatively little is known
about the relationship of zinc and female reproduction in humans.
While a small study identified long-standing infertility associated with
low serum zinc levels in several women with celiac disease, other
studies have identified no significant correlation between plasma and
follicular fluid zinc levels in fertile and infertile women (Jameson,
1976; Soltan and Jenkins, 1983; Ng et al., 1987). Indeed, a recent
study observing associations between blood metals and female fecundity in a small population of women observed a negative correlation between zinc and time to pregnancy using an adjusted Cox
proportional-hazards regression model; however, this correlation
was only borderline significant (Bloom et al., 2011). These studies
suggest zinc deficiency in women with genetic defects in zinc metabolism (celiac disease and Acrodermatitis enteropathica), physiological
stress (metallothionein synthesis), disease (diabetes, hypertension
and alcoholism) or toxicant-induced changes in zinc metabolism may
benefit from zinc supplementation if experiencing reproductive dysfunction (Weismann et al., 1979; Daston et al., 1991; Zhou et al.,
2007; Chaudhry et al., 2008).
Our increased understanding of PLCz in oocyte activation could
also be used to assist patients with rare fertility disorders. Complete
fertilization failure occurs in 1–5% of ICSI cycles, corresponding to
1000 cases per year in the UK alone (Nasr-Esfahani et al., 2010).
A deficiency in intracellular calcium oscillations is believed to be the
principle cause of this failure, with studies performed in mouse
models suggesting the technique itself leads to abnormal intracellular
calcium responses (Kurokawa and Fissore, 2003). There are now a
number of studies which demonstrate some of these fertility disorders
may be due to defective or absent spermatozoal PLCz (Heytens et al.,
2009a; Kashir et al., 2012a, b). Therefore, our increased understanding
of PLCz expression and localization within spermatozoa could be used
to generate diagnostic tools to identify this type of infertility in men
with seemingly normal sperm parameters. A deficiency in intracellular
calcium oscillations are currently treated through assisted oocyte activation (AOA) using calcium ionophores or strontium chloride (Heindryckx et al., 2008; Chen et al., 2010a; Taylor et al., 2010).
However, current AOA techniques do not mimic endogenous intracellular calcium oscillations and may be detrimental to embryo viability
Sobinoff et al.
and future offspring health. A potential alternative to these treatments
could be the addition of recombinant human PLCz protein which may
more adequately mimic endogenous mechanisms. Kashir et al. (2011)
have utilized human cell lines to produce a cell lysate containing active
recombinant human PLCz capable of eliciting calcium oscillations in
mouse oocytes characteristic of normal fertilization. Similarly, Yoon
et al. (2012) have also recently reported the use of a purified recombinant human PLCz to induce calcium oscillations in both mouse and
ICSI-failed human oocytes, although further research is required to
determine the safety of this reagent in the clinic.
In conclusion, our growing knowledge of primordial follicle activation and oocyte maturation and fertilization has allowed us to better
understand ovarian physiology and the initiation of embryogenesis.
However, important physiological questions, such as how the ovary
regulates the spatial and temporal activation of primordial follicles
and the implications of artificial oocyte activation on long-term development remain unanswered. Further investigation is required to
answer these questions and adapt our current understanding into clinical practice, providing novel diagnostics and safer and more efficient
options for therapeutic intervention to preserve fertility and treat
infertility.
Authors’ roles
All authors collaborated in preparing the manuscript and approving
the final version.
Funding
This work was supported by project grants to EAM from the Australian Research Council (DP0878355) and National Health and Medical
Research Council (510735 and 569234).
Conflict of interest
None declared
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