Developmental Biology Programme, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
Author for correspondence (e-mail:
treier{at}embl.de)
Accepted 5 November 2003
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SUMMARY |
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Key words: Transcription factor, Forkhead, Winged-helix, Folliculogenesis, Premature ovarian failure
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Introduction |
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Several different genetic mechanisms can lead to ovarian failure, including
X-chromosomal abnormalities, autosomal recessive genes causing various types
of XX gonadal dysgenesis, and autosomal dominant genes
(Schlessinger et al., 2002;
Sherman, 2000
). In contrast to
the multiplicity of possible X-linked genes, a single autosomal dominant
locus, associated with Blepharophimosis/ptosis/epicanthus inversus syndrome
[BPES (MIM 110100)], has been implicated in ovarian failure. BPES type I is
characterized by POF and a complex eyelid malformation, whereas BPES type II
patients manifest only the eyelid defect. Mutations in FOXL2, a
forkhead domain/winged-helix (WH) transcription factor, have recently been
shown to cause both types of BPES
(Crisponi et al., 2001
;
De Baere et al., 2001
). The
infertility is sexually dimorphic. Males remain fertile and transmit the trait
to the next generation.
The duration of fertility in a female is determined by the size of the
primordial follicle pool formed during fetal life and by the rate of depletion
of the pool after birth (Erickson,
2001). Primordial follicles are formed perinatally, as
pregranulosa cells encase individual oocytes within the ovary, and the entire
germ cell pool available to a female for reproduction is established. The
initial stages of folliculogenesis are independent of gonadotropins and
involve both cell-autonomous and non-autonomous factors
(Hillier, 2001
;
Kendall et al., 1995
).
Periodically, several primordial follicles simultaneously enter a growth phase
that ultimately leads to ovulation of a mature egg. Little is known about the
molecular interaction between germ and somatic cells during primordial
follicle formation, or the mechanisms that trigger the selective growth of
particular follicles in vivo (Epifano and
Dean, 2002
; Fortune et al.,
2000
; Kezele et al.,
2002
; Smitz and Cortvrindt,
2002
); although many novel insights into ovarian follicle
development have come from the study of relevant knockout mouse models
(Burns and Matzuk, 2002
;
Matzuk et al., 2002
).
We have previously reported isolation of the murine PFrk/Foxl2
gene (Treier et al., 1998).
Here we demonstrate that the sexually dimorphic ovarian-specific murine
Foxl2 gene is essential for granulosa cell differentiation and ovary
maintenance. In the absence of Foxl2, granulosa cell differentiation is
blocked at the squamous to cuboidal transition and no secondary follicles are
formed. Furthermore, we show that most if not all primordial follicles are
activated in Foxl2lacZ homozygous mutant ovaries
as demonstrated by activation of Gdf9 expression. Concurrently,
expression of two inhibitors of primordial follicle activation,
activin-ßA and anti-Mullerian inhibiting substance (Amh), is absent or
strongly diminished in Foxl2lacZ homozygous
mutant ovaries. We further provide evidence that follicles in
Foxl2lacZ homozygous mutant ovaries, once
activated, undergo apoptosis in the absence of functional granulosa cells
which leads ultimately to progressive follicular depletion and ovary atresia.
Thus, our results suggest that follicular activation is regulated by granulosa
cell function in vivo and provide a mechanism to explain the etiology of
BPES.
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Materials and methods |
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Mouse genetics
Mice were housed in specific pathogen-free and light, temperature
(21°C) and humidity (50-60% relative humidity) controlled conditions. Food
and water were available ad libitum. The procedures for performing animal
experiments were in accordance with the principles and guidelines of the
LAR/EMBL.
The targeting vector was linearized with PmeI and 30 µg vector was electroporated into E14 embryonic stem cells according to standard protocols. Cells were selected with G418 after 24 hours. Positive clones were confirmed by Southern blot using 5'- and 3'-outside probes. Two positive clones were microinjected into C57Bl/6J blastocysts and male chimeras were mated with Black Swiss (Taconic) females. Both mouse lines exhibited the same mutant phenotype. All further analysis was performed on a mixed (129/BlackSwiss/CD1) background. The Foxl2lacZ mutation has been kept by now for nine generations without any change in the phenotypic appearance on this background. Offspring were genotyped either by Southern blot or with PCR using the following primers: wild-type (WT) allele 5'-CAGATGATGGCCAGCTACCCCGAGC-3' and 5'-GTTGTGGCGGATGCTATTCTGCCAGCC-3'; mutant allele 5'-GTAGATGGGCGCATCGTAACCGTGC-3'. We intercrossed heterozygous offspring to obtain homozygous mutant mice.
Production of peptide antibody against Foxl2
A peptide antibody was produced against the first 15 aa of Foxl2
(MMASYPEPEDTAGTL) coupled to KLH and injected into rabbits.
In situ hybridization
Tissues were fixed in 10% formalin. Hybridization with
35S-labeled antisense RNA probes was done as previously described
(Treier et al., 1998) on 20
µm cryosections. Hybridization signals were detected by autoradiography
using Kodak NTB-2 liquid emulsion. Autoradiographic exposure was for 21
days.
ß-galactosidase staining and histology
ß-galactosidase staining was performed according to standard
protocols. For histological analysis tissues were fixed overnight with 4%
paraformaldehyde at 4°C, dehydrated and embedded in paraffin wax (Vogel).
Sections that were 6 µm thick were stained with Hematoxylin/Eosin.
Immunofluorescence and immunohistochemistry
We fixed tissues in 4% paraformaldehyde at 4°C overnight. Sections that
were 6 µm thick were hydrated and nonspecific binding was blocked in 5%
serum corresponding to the secondary antibody in 1xTBS + 0.4% Triton X-100.
Reactions were performed with the following primary antibodies: rabbit
polyclonal antibody against MSY2 (1:4000 dilution; kindly provided by R.
Schultz, University of Pennsylvania), rabbit polyclonal antibody against
lacZ (dilution 1:400; ICN), mouse monoclonal antibody against PCNA
(dilution of 1:200; DAKO) and rat monoclonal antibody against GCNA (undiluted;
kindly provided by G. Enders, University of Kansas Medical Center). Primary
antibodies were incubated overnight at 4°C. Successful staining for PCNA
required antigen retrieval methods. Sections were treated for 20 minutes with
2 N HCl. Slides were washed twice with TBS+0.4% Triton X-100 followed by an
incubation for one hour at room temperature with one of the following
antibodies: Alexa 488, Alexa 594 and Rhodamine Red (dilution 1:400 for all;
Molecular Probes). PCNA detection was accomplished using the M.O.M. Peroxidase
Kit (Vector Laboratories).
TUNEL assay
Ovaries were stained for apoptotic cells by a modified TUNEL method using
the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Intergen) following
the manufacturer's instructions. Sections were counterstained with Methyl
Green (Vector Laboratories).
Protein analysis
P1 ovaries were suspended in lysis buffer [100 mM Pipes pH 6.5, 150 mM
NaCl, 1% IGEPAL (Sigma), 0.05% ß-mercaptoethanol, Complete Mini (Roche)
and 10 µg/ml pepstatin (Chemicon)]. Extracts were then sonicated, spun down
on centricon columns (Millipore) and washed twice (100 mM Pipes, 100 mM NaCl,
0.05% ß-mercaptoethanol and Complete Mini). Washed extracts were diluted
in washing buffer and directly subjected to western blot analysis. For western
blot analysis, protein samples were separated by SDS-PAGE, blotted onto
nitrocellulose, and immunodetection was performed with an enhanced
chemiluminescence system (Amersham Biosciences).
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Results |
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|
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To elucidate the ovarian defect in Foxl2lacZ
homozygous mutant female mice, we first performed a histological comparison
between neonatal WT and Foxl2lacZ homozygous
mutant ovaries. Around birth, the somatic cells are recruited by germ cells
and shortly after birth, the oocytes have formed well-defined primordial
follicles in which the 12-15 µm diameter germ cells are surrounded by a
single layer of squamous or flattened granulosa cells, enclosed together
within an outer basal lamina. Comparable numbers of germ cells were present in
WT and Foxl2lacZ homozygous mutant neonatal
ovaries and primordial follicles were developed. Furthermore, we counted the
number of primordial follicles/oocytes during the first three postnatal days
in WT and Foxl2lacZ homozygous mutant ovaries and
did not observe any significant statistical difference
(Fig. 3A,B and data not shown).
Oocytes remain in the prophase of the first meiotic division until shortly
after birth when they arrest at the late diplotene or dictyate stage of the
first meiotic division. To see if the formed primordial follicles have
progressed through prophase of the first meiotic division, immunofluorescence
was performed with antibodies that distinguish specific meiotic stages of
oocyte development. Gcna1 (germ cell nuclear antigen 1) is a marker of the
germ cell lineage until they reach the diplotene/dictyate stage of the first
meiotic division, an arrested stage that persists from shortly after birth
until just prior to ovulation (Enders and
May, 1994). In contrast, expression of MSY2, encoding a
cytoplasmic RNA-binding protein, starts after oocytes have entered the
diplotene stage and persists into the dictyate stage
(Yu et al., 2001
). Antibodies
for each marker were added simultaneously to ovarian sections. Confocal
analysis revealed no difference between Foxl2lacZ
homozygous mutant and WT ovaries (Fig.
3C). In addition, no difference in FIG
expression,
a germ cell-specific transcription factor required for ovarian follicle
formation, was detected in Foxl2lacZ heterozygous
or homozygous mutant ovaries (Soyal et
al., 2000
) (data not shown).
|
|
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Molecular characterization of the follicle defect
To further investigate the molecular defects underlying the
Foxl2lacZ homozygous mutant phenotype, we used
35S-in situ hybridization analysis to visualize the expression of
molecules crucial for folliculogenesis
(Fig. 6). Foxl2 itself
is expressed in granulosa cells during folliculogenesis. Using an in situ
probe localized in the 5'-non-deleted region of Foxl2, we
followed its expression in WT and Foxl2lacZ
homozygous mutant ovaries (Fig.
6A). Foxl2 expression was indistinguishable between WT
and mutant newborn ovaries at P1. In 2-week-old ovaries, Foxl2
expression was strong in preantral follicles. In contrast, mutant ovaries
displayed a more uniform expression consistent with the altered morphological
appearance. In 16-week-old mutant ovaries Foxl2 expression declined
to low levels.
|
It has been shown that murine folliculogenesis is regulated by the
interplay of Kit ligand (Kitl) and growth differentiation factor 9 (Gdf9), a
TGF-ß family member, once a primordial follicle is activated. Gdf9 is an
oocyte-derived growth factor synthesized from the primary one-layer or type 3a
follicle stage until after ovulation and required for somatic cell function in
vivo (Dong et al., 1996;
Elvin et al., 1999
).
Unexpectedly, at P14 most if not all oocytes in
Foxl2lacZ homozygous mutant ovaries had activated
Gdf9 expression (Fig.
6G). This indicates that almost all follicles have already
initiated folliculogenesis at this stage
(Elvin et al., 1999
).
Kitl is expressed in pregranulosa and granulosa cells and is essential for
survival and proliferation of primordial germ cells and has also been
implicated in initial primordial follicle activation
(Bedell et al., 1995;
Huang et al., 1993
;
Klinger and De Felici, 2002
).
Interestingly, Kitl was strongly expressed throughout all analysed
stages and even persisted at high levels in 16-week-old
Foxl2lacZ homozygous mutant ovaries
(Fig. 6H).
Several structural cell surface molecules (e.g. E-cadherin, connexin37,
connexin43, 6 and ß1 integrins) have been implicated in early
ovarian folliculogenesis (Ackert et al.,
2001
; Burns et al.,
2002
; Di Carlo and De Felici,
2000
; Simon et al.,
1997
). RT-PCR did not reveal any qualitative differences in the
expression of these molecules between Foxl2lacZ
homozygous mutant ovaries and WT ovaries at P1 (data not shown).
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Discussion |
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Factors that trigger the primordial to primary follicle transition in vivo
are largely unknown, although somatic cell-derived Kitl and Amh are implicated
in the regulation of this process
(Durlinger et al., 2002;
Klinger and De Felici, 2002
;
Parrott and Skinner, 1999
).
Furthermore, it has been suggested that factors secreted from late stage
follicles modulate the activation of primordial follicles
(Durlinger et al., 2002
;
Mizunuma et al., 1999
). Most
notably Amh and activin-ßA have been proposed as inhibitory factors,
whereas follistatin secreted by cuboidal granulosa cells would protect early
follicles from inhibition (Braw-Tal,
2002
). The absence or significant downregulation of the inhibitory
factors, activin-ßA and Amh, coincides with the precocious activation of
almost all primordial follicles in Foxl2lacZ
homozygous mutant ovaries two weeks after birth, as demonstrated by activation
of Gdf9 expression in oocytes. Neonatal rat ovaries cultured in the
presence of Kitl display a higher rate of primordial to primary follicle
transition (Klinger and De Felici,
2002
; Parrott and Skinner,
1999
). Thus, the high expression level of Kitl in the
absence of inhibitory factors in Foxl2lacZ
homozygous mutant neonatal ovaries is consistent with the proposed role for
Kitl in primordial follicle activation in vivo. Together these data indicate
that suppressors of initial primordial follicle activation such as
activin-ßA and Amh expressed by advanced follicles may regulate the
primordial to primary follicle transition in vivo, supporting the proposed
model that initially oocyte growth follows, rather than precedes, the changes
in granulosa cells (Braw-Tal,
2002
; Fortune et al.,
2000
; Kezele et al.,
2002
). However, further studies will have to show if additional,
as yet unknown Foxl2-regulated suppressors of primordial follicle activation
exist that are absent in Foxl2lacZ homozygous
mutant ovaries. In this respect it is noteworthy that another distantly
related WH/forkhead transcription factor Foxo3a has also recently been
implicated as a suppressor of ovarian follicle activation
(Castrillon et al., 2003
). It
will be interesting to determine in the future if Foxo3a and Foxl2 share
common target genes that are required to maintain primordial follicles in a
dormant state.
Subsequent to the initial primordial follicle recruitment, bidirectional
signaling between oocytes and surrounding somatic cells is critical for the
progression beyond the primary follicle stage
(Matzuk et al., 2002).
Molecules important in this cross-talk include Gdf9, which is secreted by
oocytes, and again Kitl, which is produced by the granulosa cells
(Driancourt et al., 2000
). It
has been shown that the mammalian oocyte orchestrates the rate of ovarian
follicle development once the paracrine oocyte factors Gdf9 and BMP-15 have
been activated (Eppig and O'Brien,
1996
; Eppig et al.,
2002
; Yan et al.,
2001
). Despite the high expression of Gdf9 and
Kitl in Foxl2lacZ homozygous mutant
ovaries, proliferation of granulosa cells is almost absent, suggesting that
only cuboidal granulosa cells may be responsive to mitogenic factors such as
Gdf9 secreted from the oocyte. However, the high level of Kitl
expression maintained in the mutant ovaries may explain the slow degeneration
of the oocytes and the presence of very few degenerated oocyte remnants in
16-week-old Foxl2lacZ homozygous mutant
ovaries.
Although folliculogenesis in Gdf9 knockout animals is arrested
around the same stage as in Foxl2lacZ homozygous
mutant ovaries, there are noticeable phenotypic differences. In the
Gdf9 mutant ovaries the oocyte overgrows and is surrounded by up to
two layers of cuboidal granulosa cells before atresia occurs
(Dong et al., 1996;
Elvin et al., 1999
). In
contrast, we never observe follicles with a healthy-looking oocyte surrounded
by two layers of cuboidal granulosa cells in
Foxl2lacZ homozygous mutant ovaries. However,
both factors, Gdf9 and Foxl2, are required for granulosa cell proliferation.
Nevertheless, the more severe ovarian phenotype of
Foxl2lacZ homozygous mutant mice compared with
Gdf9 mutant mice suggests that Foxl2 is involved in additional
transcriptional networks. Indeed, molecules such as bFGF and EGF/TGF-
may play complementary roles in these processes and Foxl2 may be the signaling
integrator in the nucleus (Nilsson et al.,
2001
; Qu et al.,
2000
).
It has recently been reported that Foxl2 is not only expressed in
somatic cells but also in female germ cells and oocytes during ovarian
development (Loffler et al.,
2003). However, we cannot detect any expression of Foxl2 in germ
cells/oocytes similar to what has been observed in other studies
(Cocquet et al., 2002
). In
addition, we also do not observe lacZ expression of our
Foxl2lacZ allele in germ cells/oocytes, which
otherwise faithfully recapitulates the Foxl2 in situ expression pattern in the
whole embryo during development.
Foxl2, in combination with Gata2 and follistatin, is one
of the earliest sexually dimorphic genes expressed specifically in the ovary
(Menke and Page, 2002;
Siggers et al., 2002
) and one
of two genes affected in the goat polled intersex syndrome (PIS)
(Pailhoux et al., 2001
). BPES
female patients clearly show no sex reversal. However, they are only
haploinsufficient for the FOXL2 mutation. Our results clearly
demonstrate that complete loss of Foxl2 protein function in the mouse is not
sufficient to lead to XX sex reversal in female mice. However, it will be
interesting to see whether a role for Foxl2 in primary sex determination will
be revealed on a sensitized background for sex determination. Nevertheless,
the expression pattern of Foxl2 together with the results obtained
from the Wnt4 knockout model, supports the current trend toward a
change in the dogma that ovary development is the default pathway of gonadal
differentiation (Vainio et al.,
1999
).
In conclusion, the observed infertility in Foxl2lacZ homozygous mutant females can be explained by the early depletion of the primordial follicle pool. This depletion is because of a premature activation of almost all primordial follicles as a result of granulosa cell differentiation failure and leads to widespread follicular atresia. The absence of activin-ßA and Amh, two suppressors of initial follicle recruitment, may contribute to the observed general loss of follicular quiescence in Foxl2lacZ homozygous mutant ovaries.
So far, mutations in eight different forkhead genes have been associated
with human developmental disorders
(Carlsson and Mahlapuu, 2002).
BPES is, to date, the only human autosomal dominant disorder found associated
with POF, a disease that affects 1% of women
(Pal and Santoro, 2002
;
Schlessinger et al.,
2002
).
Our analysis of Foxl2lacZ homozygous mutant ovaries has provided novel insights into the activation of primordial follicles and ovarian maintenance in vivo and may explain the underlying pathophysiological mechanisms leading to POF in BPES patients. Mouse models of POF such as the Foxl2lacZ knockout mouse described here will facilitate the identification of additional factors regulating ovarian follicle activation, a process crucial in reproductive biology, and the development of improved contraceptives and potential therapeutic treatments for POF.
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ACKNOWLEDGMENTS |
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![]() |
Footnotes |
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Present address: Center for Oral Biology, University of Rochester School of
Medicine and Dentistry, 601 Elmwood Avenue, Box 611, Rochester, NY 14642,
USA
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