Cellular basis for paracrine regulation of ovarian follicle

Abstract

Paracrine factors secreted by oocytes and somatic cells regulate many important aspects of early ovarian follicle development in mammals. From activation of dormant primordial follicles to selection of secondary follicles, locally acting factors have been identified that appear to exert important effects on the growth and differentiation of oocytes and granulosa cells. This article summarizes evidence to support a model for bi-directional paracrine communication that is based on developmental regulation of the delivery and reception of paracrine factors at the oocyte-granulosa cell interface. Transzonal projections that originate from granulosa cells and terminate at the oocyte plasma membrane provide a polarized means to orient the secretory organelles of somatic cells. Characterization of transzonal projections in follicles from normal and genetically modified mice reveals dynamic changes in the density and stability of transzonal projections. On the basis of new data analysing the orientation and cytoskeletal content of transzonal projections in mammalian oocytes, a model is proposed for regulation of paracrine growth factor secretion by follicle-stimulating hormone. These findings have immediate implications for ovarian hyperstimulation protocols and follicle culture models as related to the production of mammalian embryos by assisted reproductive technologies.

Full text

Although the physiological, molecular and genetic deter-
minants that initiate and sustain follicular growth and
maturation have received much attention (see reviews
by McNatty
et al
., 1999; McGee and Hsueh, 2000),
comparatively little information has been forthcoming with
regard to the changes in cellular behaviour that attend the
process of folliculogenesis. When viewed in the context of
other developmental systems, in which paracrine control of
cell differentiation is considered implicitly relative to cell
signalling, cell–cell adhesion and cell–extracellular matrix
(ECM) interactions, our knowledge of cellular behaviours in
the ovarian follicle is lacking, despite the wealth of
information available on the role of growth factors and
hormones in ovarian follicle development (for a review see
Elvin and Matzuk, 1998). Recently, Rodgers
et al.
(1999,
2000) have drawn attention to the role of the ECM during
bovine follicle growth as related to changes in the follicular
basal lamina that may influence the growth and
differentiation of both granulosa and theca cells. Given the
general importance of the ECM in regulating diverse cell
behaviours including migration, division, adhesion and
death, this direction of study will add measurably to our
understanding of the cellular forces that shape remodelling
of the follicle during normal growth, differentiation and
atresia.
In the context of paracrine factor access and presentation
to target cells, it is helpful to consider the disposition of the
ECM relative to the three basic types of cell present in
preantral follicles. Although much of the growth of preantral
follicles is characterized by gradual expansion of the
follicular basal lamina as oocyte size and the number of
granulosa cells increase, thecal cells also associate with the
follicle and begin their course of differentiation. Given that
growth factors such as growth differentiation factor 9 (GDF-
9) and kit ligand (KL) have been implicated in the paracrine
control of early follicle development (Yoshida
et al
., 1997;
Elvin and Matzuk, 1998; Elvin
et al.
, 1999a; Galloway
et al.
,
2000), it is essential to consider the cellular origins and
targets of signalling molecules in relation to the cell–ECM
interfaces present at these early stages. The follicular basal
lamina encapsulates granulosa cells and separates these
cells from the surrounding theca cells, which are encased
by basal lamina-like material (see Rodgers
et al
., 2000). The
Cellular basis for paracrine regulation of ovarian follicle
development*
David F. Albertini, Catherine M. H. Combelles,
Elizabeth Benecchi and Mary Jo Carabatsos
Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston,
MA 02111, USA
Paracrine factors secreted by oocytes and somatic cells regulate many important aspects
of early ovarian follicle development in mammals. From activation of dormant primordial
follicles to selection of secondary follicles, locally acting factors have been identified that
appear to exert important effects on the growth and differentiation of oocytes and
granulosa cells. This article summarizes evidence to support a model for bi-directional
paracrine communication that is based on developmental regulation of the delivery and
reception of paracrine factors at the oocyte–granulosa cell interface. Transzonal
projections that originate from granulosa cells and terminate at the oocyte plasma
membrane provide a polarized means to orient the secretory organelles of somatic cells.
Characterization of transzonal projections in follicles from normal and genetically
modified mice reveals dynamic changes in the density and stability of transzonal
projections. On the basis of new data analysing the orientation and cytoskeletal content of
transzonal projections in mammalian oocytes, a model is proposed for regulation of
paracrine growth factor secretion by follicle-stimulating hormone. These findings have
immediate implications for ovarian hyperstimulation protocols and follicle culture models
as related to the production of mammalian embryos by assisted reproductive
technologies.
© 2001 Journals of Reproduction and Fertility
1470-1626/2001
Reproduction
(2001) 121, 647–653 Review
Email: david.albertini@tufts.edu
*This review is based on a symposium talk given at the meeting of
the Society for the Study of Fertility held at the Edinburgh
International Conference Centre from 31 July to 2 August 2000.

‘personalized’ ECM of the oocyte, the zona pellucida, also
becomes highly organized and serves to limit contact
between the oocyte and surrounding granulosa cells. If
oocytes, granulosa and theca cells act as cellular sources or
receivers of paracrine growth factors like GDF-9 or KL,
there must be mechanisms for the bi-directional exchange
of such factors through these intervening matrices. Given
this problem of the spatial partitioning of discrete types of
cell by the ECM, and the well-known role of the ECM as a
selective filtration or barrier device, this article reviews
what is known about the oocyte–granulosa cell interface
with respect to cellular mechanisms that could facilitate
and regulate bi-directional exchange of paracrine signals
(Buccione
et al.
, 1990).
Transzonal projections at the oocyte–granulosa cell
boundary
Transzonal projections (TZPs), follicle cell extensions that
traverse the zona pellucida and terminate on the oocyte cell
surface, have been well characterized in many mammals by
electron microscopy (Hertig and Adams, 1967; Anderson and
Albertini, 1976; reviewed in Motta
et al
., 1994). The studies
of Motta
et al.
(1994) on human ovarian follicles were the first
to demonstrate that dynamic alterations in the number and
form of TZPs occur at specific stages of follicle development
and might serve to co-ordinate or modulate information
exchange between the oocyte and follicle cells. This work
showed that, in preantral follicles, TZPs were most numerous
forming both adhesive and gap junctional contacts at the
oolemma, and further demonstrated that during peak periods
of oocyte growth, TZPs extended as deep invaginations that
impinged upon the germinal vesicle. After further antral
follicle development, TZPs retracted and maintained fewer
terminal connections with the oocyte than in preantral
follicles. During ovulation, active retraction of TZPs was
noted (Motta
et al.
, 1994).
These seminal findings merit reinterpretation given recent
observations on the composition and structure of TZPs and
assembly of the zona pellucida. The continued synthesis and
secretion of zona pellucida proteins throughout ovulation
indicates that remodelling of the zona pellucida is an
ongoing process during folliculogenesis (Wassarman and
Albertini, 1994). Since there is abundant evidence consistent
with the contention that cumulus cell uncoupling from the
oocyte involves TZP retraction and remodelling during
maturation of cumulus–oocyte complexes
in vivo
and
in
vitro
(Allworth and Albertini, 1993; Albertini and Rider,
1994; Suzuki
et al
., 2000), the continued synthesis and
secretion of zona proteins may allow for closure of channels
left after cellular retraction. Thus, marked changes in
granulosa–oocyte and granulosa–granulosa cell adhesion,
induced by the LH surge at ovulation, co-ordinate changes
in the shape and secretory activity of cumulus cells with the
final stages of oocyte and follicle maturation. But what about
earlier transitions in follicle development?
Differences in gonadotropin-dependent events in antral
follicle development, during what McGee and Hsueh
(2000) refer to as cyclic recruitment, probably involve very
different signalling requirements compared with the initial
recruitment of primordial follicles into the growing pool of
preantral follicles. Plasticity and remodelling of the zona
pellucida may similarly allow for regulated changes in the
establishment and maintenance of functional TZPs during
these different critical transitions of follicle development.
The observations of Motta
et al
. (1994) on preantral
follicles should be considered in light of the predominant,
but not exclusive, role of known paracrine factors during
these early developmental stages. TZPs were reported to be
most abundant in preantral follicles. Studies in our
laboratory have defined functional properties of TZPs in
preantral follicles that would support their role in the
localized secretion or uptake of factors at the oocyte–
granulosa cell interface (Can
et al.
, 1997). Numerous
microtubule-containing TZPs are present within the zona
pellucida in preantral follicles as evidenced by optical
sectioning of intact follicles by confocal microscopy (Fig.
1a). Moreover, mitochondrial vital staining of intact
cultured mouse follicles with MitoTrackerTM shows active
bi-directional movements of these organelles within TZPs
when monitored by time-lapse confocal microscopy (Fig.
1b). Similarly, loading follicles with non-metabolizable and
neutral charge endocytic tracers like fluorescent dextrans
shows active translocations of endosomes and lysosomes
across the zona pellucida due to organelle movement
within TZPs (Fig. 1c). These findings extend ultrastructural
observations on the organellar contents of TZPs and
document their capacity to support polarized organelle
movement, an observation consistent with the demon-
stration of microtubules within TZPs and the role of
microtubules in directed organelle movement (Allworth
and Albertini, 1993; Can
et al.
, 1997; Carabatsos
et al
.,
1998). If these structures mediate directed transport,
secretion, or selective uptake of factors secreted by the
oocyte (for example GDF-9), it would be expected that
granulosa cells apposed to the zona pellucida would be
anchored and oriented to support localized macromol-
ecular exchange. This contention is supported by electron
microscopy of normal follicles and follicles from mutant
lines of mice blocked at various stages of preantral
development.
In control mice, TZPs observed in preantral follicles are
anchored by F-actin bearing follicle cell extensions at the
periphery of the zona pellucida, but send solitary and
usually corkscrew-shaped projections through the zona
pellucida (Fig. 2a). Follicles from GDF-9 null (–/–) animals
lack anchoring TZPs but show prominent organelle-rich
TZPs that envelope the oocyte surface, indicating that, in
this situation, an unregulated exploration of the oocyte is
allowed to occur (Carabatsos
et al
., 1998; Fig. 2b). In
marked contrast, animals null for the FSH-βgene, in which
follicle development is arrested at the late secondary
preantral stage (Kumar
et al
., 1997), show prominent
organelle-rich and anchoring TZPs (Fig. 2c). Furthermore,
648
D. F. Albertini
et al.

the centrosome–Golgi complex is oriented towards the
oocyte in nearly all follicle cells apposed to the outer
surface of the zona pellucida in this FSH-β-deficient animal
model (Fig. 2c). Thus, in the absence of FSH, follicle arrest
at the secondary stage is associated with a striking degree of
granulosa cell polarity that spatially approximates the
secretory machinery with an increased density of TZPs. The
implications of this finding are discussed below with respect
to processing, secretion and transcytotic transport of factors
between oocyte, granulosa and theca. In addition, a central
question that emerges from observations of enhanced input
in the absence of FSH-βis: what regulates the orientation
and stability of TZPs?
Factors regulating TZP stability
As noted earlier, changes in cell–cell (junctional) and
cell–zona adhesion underscore both the retraction of TZPs
and the migration of cumulus cells during hormone-induced
expansion (Albertini and Rider, 1994), and, in some systems,
selective loss of anchoring of granulosa cells to the zona
pellucida is associated with invasion of microtubule TZPs
during hormone-induced oocyte maturation (Allworth and
Albertini, 1993). As in axons, microtubules form the cy-
toskeletal core of granulosa cell TZPs and would provide
tracks for the polarized translocation of secretory pathway
organelles. Thus, it is important to consider factors intrinsic
to granulosa cells that influence the stability of TZPs, since,
as indicated earlier, developmental changes in their stability
would have direct consequences on the processing and
action of paracrine factors originating from the oocyte or
somatic follicular cells.
One mechanism for stabilizing microtubules involves
post-translational acetylation of the α-tubulin subunit that
occurs subsequent to microtubule polymerization (Can and
Albertini, 1997). Cultured human ovarian granulosa cells
show a subpopulation of drug-resistant acetylated micro-
tubules (Can and Albertini, 1997) and these are present in
human cumulus cells. Typically, all TZPs present in the
zona pellucida of human oocytes retrieved for
in vitro
fertilization show acetylated microtubules (Fig. 3). In
addition to the staining observed within branching TZPs,
staining is found within circular hoop-like structures that
represent terminal portions of TZPs which associate with
the oocyte surface (Fig. 3b, arrows). Thus, the prevalence of
acetylated microtubules within TZPs of human oocytes
indicates that this mechanism for maintaining microtubule
stability may persist through the latest stages of follicle
development to maintain oocyte–granulosa cell connections
during cumulus expansion. This mechanism for TZP
stabilization has been evaluated in follicles at earlier
developmental stages.
Paracrine regulation of ovarian follicle development
649
Fig. 1. Confocal microscope images of intact preantral mouse ovarian follicles. (a) Dense network of
microtubule-containing transzonal projections (TZPs) derived from follicle cells (arrows). (b) A single
confocal image of vitally stained mitochondria within a follicle cell TZP (arrow) obtained from a living
cultured follicle labelled with MitoTrackerTM. (c) Fluorescent dextran-labelled endosomes (arrows)
within follicle cell TZPs from a follicle cultured in the presence of endocytic marker before fixation and
analysis by confocal microscopy. ZP: zona pellucida. Scale bars represent 5 µm.

A similar approach was used to analyse TZPs in preantral
mouse follicles with respect to the possible consequences of
protein kinase A activation in granulosa cells, one of the
most important signalling pathways invoked to regulate
granulosa cell differentiation (McGee and Hsueh, 2000).
Untreated oocytes isolated from preantral follicles of
prepubertal mice show a high density of TZPs that are
enriched in the acetylation epitope (Fig. 4a,b). Brief
treatments with the phosphodiesterase inhibitor isobutyl-
methylxanthine (IBMX), an agent commonly used to
increase intracellular cyclic monophosphate concentra-
tions in granulosa cells, causes both a reduction in TZP
density and a decrease in immunodetectable acetylated
tubulin (Fig. 4c,d). Together, these observations imply that
TZPs are dynamic granulosa cell structures, the stability and
function of which may be subject to both developmental
and hormonal regulation. As specialized conduits for the
transport, processing and reception of paracrine factors at
the oocyte–granulosa cell interface, TZPs may represent a
novel mechanism for the regulation of paracrine signalling
in the developing follicle. A model for this hypothesis is
presented below.
Regulation of paracrine signalling
Given the importance of modulating local forms of cell
communication within the developing ovarian follicle,
especially with respect to the changing demands for
oocyte–granulosa cell cross talk at different developmental
stages, this review of cellular behaviours has focused on
650
D. F. Albertini
et al.
Fig. 2. Electron micrographs of the oocyte–granulosa cell interface
from control (a), growth differentiation factor 9 (GDF-9) null (b) or
FSH-βnull (c) mouse preantral follicles. In control follicles,
anchoring projections (AP) and zona-traversing projections (TZP)
are evident (a). Prominent organelle-rich TZPs (arrow) are typical
in GDF-9 null follicles (b). Follicles from FSH-βnull animals show
a striking degree of granulosa cell orientation towards the oocyte as
evidenced by the apposition of the centrosome–centriole complex
(c, arrowheads). Scale bars represent 1 µm.
Fig. 3. Comparison of total tubulin (a) and acetylated tubulin (b)
staining patterns within zona-enclosed human oocytes retrieved
for
in vitro
fertilization. Note the abundance of oocyte
microtubules (a) that lack acetylated α-tubulin epitope after
immunostaining compared with those within TZPs with acetylated
α-tubulin epitope (b). TZPs containing acetylated microtubules
often terminate as hoops (arrows) that are located at the oocyte
surface. Scale bar represents 20 µm.

two important points. First, modifications in cell–cell and
cell–matrix interactions are likely to influence both the
availability and actions of growth factors derived from each
of the cellular compartments of the follicle (oocyte,
granulosa and theca). Thus, the architectural remodelling
associated with oocyte growth, epithelial expansion,
antrum formation and differentiation of a vascularized theca
represents significant consequences of differential gene
expression that both reinforce functional distinctions in the
germ and somatic cell lineages of the follicle and co-
ordinate the processes of oogenesis and folliculogenesis.
Second, since oocyte development is a critical aspect of
follicle development and oocytes exert profound effects on
granulosa cells, the interface between oocyte and granulosa
cell emerges as a major control site for the co-ordination
of follicle development. Historically, the properties of
this interface have been viewed as fundamental to the
regulation of oocyte growth and maturation and follicular
luteinization (Elvin
et al.
, 1999a,b, 2000; Mermillod
et al.
,
1999; Nagyova
et al.
, 2000). Here, we provide a novel
framework for considering aspects of paracrine signalling
that would depend directly on dynamic changes in the
connections between oocyte and granulosa cells.
On the basis of work summarized earlier in this review,
the model proposed (see Fig. 5) has been developed to
explain how the interplay between growth factors and
hormones may mediate the selection, support and demise
(atresia) of the follicle. Implicit in this model is the notion
that TZPs serve as specialized devices for mediating
information exchange between oocyte and granulosa cells.
This exchange includes, but is not limited to, the exchange
of small molecules via gap junctions that support metabolite
exchange. Thus, in preantral follicles, in which oocyte
growth is supported and follicle growth is protracted, bi-
directional exchange of cytoplasmic signals, whether
nutrients or second messengers, co-ordinates directly certain
aspects of metabolism shared by oocytes and granulosa cells
(Buccione
et al.
, 1990). Possibly just as important is the need
to establish and maintain terminal TZP connections that
would mediate both the local delivery of growth factors and
possibly facilitate receptor occupation and activation by
ligands like KL, a granulosa cell product (Yoshida
et al.
,
1997; Elvin
et al.
, 1999a). Delivery of follicle cell-derived
leptin and STAT3 to the oocyte by TZPs has been reported
(Antczak and Van Blerkom, 1997). TZPs would also support
uptake of oocyte products, like oocyte-specific members of
the transforming growth factor βsuperfamily (GDF-9),
which could be transported and possibly processed during
transcytosis through granulosa cells for presentation to more
distal granulosa cells and even surrounding theca (Dube
et
al.
, 1998; Solovyeva
et al.
, 2000). Central to this model are
key properties of TZPs: (i) that they possess the appropriate
subcellular machinery for orienting the trafficking of
paracrine factors; and (ii) that their dynamics are controlled
by other factors (for example FSH) such that localized
delivery and uptake is regulated. It appears that criteria to
support the idea of polarized secretion and endocytosis
have been met, at least on a preliminary level and, as the
model proposes, FSH may be one factor causing TZP
retraction given the data mentioned above.
In many ways, TZPs resemble axons, as has been
previously alluded to (Allworth and Albertini, 1993), and
recent data indicate additional similarities to synapse-like
modes of signal transmission (Grosse
et al.
, 2000). The
cytoskeletal composition, organellar contents and overall
disposition of TZPs at the oocyte–granulosa cell interface
(Motta
et al.,
1994) support a view consistent with TZPs
functioning in the directed delivery and uptake of factors
within the perivitelline space. Although future work will be
needed to define the factors involved in the formation and
function of TZPs, especially with respect to the actions of
GDF-9, KL and related signalling molecules, there is already
some evidence to support their role in the acquisition of
developmental competence by mammalian oocytes (Liu
et
al.
, 1997; Carabatsos
et al.
, 1998; Mermillod
et al.
, 1999).
As mentioned, Antczak and Van Blerkom (1997) have
shown that leptin and STAT3, factors that may influence
embryo metabolism, assume a polarized distribution in
oocytes and embryos. On the basis of confocal microscopy
studies in intact follicles, it was proposed that leptin and
STAT3 are maternally derived from a subpopulation of
Paracrine regulation of ovarian follicle development
651
Fig. 4. Effects of isobutylmethylxanthine (IBMX) on the density and
tubulin acetylation of TZPs in mouse oocytes isolated from
preantral follicles. Total tubulin (a) and acetylated tubulin (b) in
control oocytes cultured for 2 h before fixation and processing.
(c,d) Respective tubulin patterns after exposure to 100 µmol IBMX
l–1 for 2 h; note the reduction in TZP density and expression of
acetylation epitope. Scale bar represents 20 µm.

follicle cells and that TZPs deliver these products into the
perivitelline space for endocytosis by the oocyte.
The extent to which these and other protein factors
secreted by granulosa cells gain access to the oocyte needs
to be investigated more thoroughly given current ART
protocols that involve removal of somatic cells. This
commonly practised manipulation may compromise
efficient delivery of factors to the oocyte at crucial stages of
development that normally would have been subserved by
the function of TZPs proposed here. In light of the data
presented herein, the success of hormone-induced follicle
development
in vivo
or
in vitro
may depend on exper-
imental protocols that maintain the structural integrity of the
granulosa–oocyte cell interface (Hayashi
et al.
, 1999).
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