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Division of Neuroscience (G.A.D., C.R., S.R.O.), Oregon Regional Primate Research Center/Oregon Health Science University, Beaverton, Oregon 97006-3448; and Department of Anatomy and Cell Biology (A.N.H.), University of Maryland, Baltimore, Maryland 21202
Address all correspondence and requests for reprints to: Sergio R. Ojeda, Division of Neuroscience, Oregon Regional Primate Research Center, 505 NW 185th Avenue, Beaverton, Oregon 97006-3448. E-mail: ojedas{at}ohsu.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies of the rodent ovary have shown that, like the process of follicular assembly itself, the initial growth of primordial follicles is a gonadotropin-independent process (12, 13). In rats and mice, follicular assembly is an explosive phenomenon that takes place during the second and third day of postnatal life (14, 15). The changes in cellular organization are dramatic: at birth only 1 or 2 primordial follicles are detected in the entire ovary; 2 days later the number of follicles has increased to more than 1,000 (15), so that by postnatal day 3 most oocytes are enclosed in follicles, and the newly formed follicles begin to grow by acquiring additional layers of granulosa cells (14). While in recent years some of the molecules required for the generation of germ cells and their survival have been identified (16, 17, 18), only two signaling molecules, the c-kit ligand produced by pregranulosa cells and the oocyte-derived growth factor GDF-9, have been shown to be required for the initial growth of follicles (19, 20). Because NGF and its receptors are present in nonneural cells of the perinatal rat ovary, it has been suggested that NGF may play a role in the control of early follicular development (7). The present results provide experimental evidence in support of this view.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immunohistofluorescence-confocal microscopy
Immunohistochemical detection of trkA and
p75NTR was performed using 14-µm cryostat
sections from 7-day-old ovaries collected from both
NGF-/- and wild-type littermates and fixed by
immersion in Zamboni’s fixative (7). trkA was detected
with a rabbit polyclonal antibody (trkA-RTA; kindly provided by
Drs. Baoji Xu and Louis Reichardt, Howard Hughes Medical Institute,
University of California, San Francisco, CA), shown earlier to
specifically recognize the trkA receptor (22, 23);
p75NTR was detected with monoclonal antibody 192
IgG (24), purchased from Chemicon International (Temecula,
CA; Mab 365). The specificity of this antibody has also been
demonstrated earlier (9, 25, 26). The ovarian sections
were incubated overnight at 4 C with the antibodies diluted at 1:2000
(trkA-RTA) and at 1:1000 (192 IgG), and the immunoreaction was
developed the next day with fluorochrome-tagged secondary antibodies. A
Texas Red-conjugated goat antimouse gamma globulin (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA; 1:200, 1
h at room temperature) was used to detect p75NTR, and
fluorescein-conjugated goat antirabbit gamma globulin (1:200, also from
Jackson ImmunoResearch Laboratories, Inc.) to detect trkA.
Control sections were incubated in the absence of either primary
antibody. Cell nuclei were stained with the vital dye Hoechst
(Molecular Probes, Inc., Eugene, OR; 1 µg/ml 0.02
M potassium phosphate buffer containing 0.9% sodium
chloride).
Confocal images were acquired using a Leica Corp. TCS SP confocal system (Leica Corp. Microsystems, Heidelberg, Germany) using a 40x Plan Apochromat objective with 1.25 numerical aperture. Hoescht, fluorescein, and Texas Red were imaged simultaneously, using the 361- and 488-nm lines of two argon lasers and the 568-nm line of a krypton laser for excitation. The intensity of each excitation line was adjusted so that the contribution of each fluorophore in neighboring channels was negligible. In general, four to eight optical sections were acquired for each image. Colors were merged and sections were projected into a single plane using MetaMorph 4.5 (Universal Imaging Co., West Chester, PA). Images were further processed and printed using Photoshop 5.5 (Adobe Systems, San Jose, CA).
Hybridization histochemistry
The procedure employed was based on the method of Simmons
et al. (27) and was carried out as reported
previously (7, 9) using a
35S-uridine triphosphate-labeled trkA
complementary RNA probe previously shown to identify trkA
messenger RNA (mRNA) in the rat ovary (3, 7). Upon
collection, the ovaries were immediately fixed by immersion in 4%
paraformaldehyde-0.1 M sodium borate buffer (pH
9.5; overnight at 4 C). Thereafter, they were embedded in OCT
compound (Miles Inc., Elkhart, IN) and frozen on dry ice. The
hybridization was performed on 10-µm cryostat sections, as reported
previously (7). Control sections were incubated with the
sense trkA RNA probe. Following development of the hybridization
signal, the sections were counterstained with thionin.
Morphometric analysis
The ovaries of 7-day-old mice were fixed in Kahle’s fixative
(28), embedded in paraffin, serially sectioned at 6 µm,
stained with Weigert’s iron hematoxylin, and counter-stained with
picric acid-methyl blue. Every third section was imaged on a Carl Zeiss Axioplan (Carl Zeiss, Jenna, Germany), using
a CoolSnap camera (Roper Scientific, Stillwater, MN). Follicles were
counted using the manual count feature of MetaMorph (Universal Imaging
Co.). Only follicles in which the nucleus of the oocyte was visible
were counted (11). The total number of follicles per ovary
was estimated as reported (15).
Assessment of proliferation
The ovaries from newborn (day of birth) mice were fixed in
Carnoy’s fixative, embedded in paraffin, sectioned at 4 µm, and
subjected to immunohistochemistry for proliferating cell nuclear
antigen (PCNA). To enhance antigen retrieval, the sections were
microwaved for 3 min in sodium citrate buffer (Antigen Retrieval Citra;
BioGenex Laboratories, Inc., San Ramon, CA) as recommended
(29), before incubation with the primary antibody. PCNA
was identified with a monoclonal antibody (Mab PC-10, 1:1,000 dilution;
Santa Cruz Biotechnology, Inc., Santa Cruz, CA). The
immunoreaction was developed by incubating the sections for 5 min with
a
diaminobenzidine/H2O2/nickel
chloride solution (30). In other experiments the ovaries
from NGF+/+ and NGF-/-
mice were explanted on the day of birth into an organ culture system
(31) and incubated with 100 µM
bromodeoxyuridine (BrdU) for 24 h at 37 C in an atmosphere of 60%
oxygen, 35% nitrogen, and 5% CO2, as reported
previously (31). At the end of this period, the ovaries
were processed for BrdU immunohistochemistry, which was performed as
outlined for PCNA, but using a monoclonal antibody to BrdU (Mab B-2531,
1:1,000 dilution; Sigma, St. Louis, MO). Every fifth
section (periodicity = 20 µm) was imaged with a Sony DKC-5000
digital camera (Sony Corp., Tokyo, Japan) attached to a
Nikon Eclipse E600 microscope using a Plan 40x NA 0.65
objective (Nikon Inc., Melville, NY). Positive cells were
counted using the manual feature of MetaMorph. In the case of PCNA
staining, mesenchymal cells were differentiated from epithelial cells
by morphological criteria (28), as the nuclei of the
former are elongated, whereas those in the latter are round. Ovarian
volumes were estimated by measuring the area of each section used for
counting and multiplying the sum of all measured areas by 20 µm, the
distance between adjacent measured sections.
Measurement of serum gonadotropins
Circulating LH and FSH levels were measured by RIAs using
reagents provided by the NIH National Pituitary Agency.
Data analysis
The differences in follicle numbers, gonadotropin
concentrations, and numbers of proliferating cells were analyzed using
one-way ANOVA and the Student-Newman-Keuls multiple test for individual
means (when there were more than two groups).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A–E), with a
distribution pattern similar to that previously observed in the
feto-neonatal rat ovary (7). The trkA receptor
(green immunofluorescence) was also present in
prethecal-interstitial cells, but in a much more restricted pattern of
expression (Fig. 1, A and B, arrowheads show trkA-positive
prethecal and interstitial cells, respectively). Unexpectedly, trkA
immunostaining was also detected in granulosa cells and oocytes (Fig. 1, A and B, D and E). The abundance of trkA immunoreactivity in
granulosa cells varied between follicles, appearing to be greater in
primary follicles (Fig. 1, B and E) than in follicles with more than
one layer of granulosa cells (Fig. 1, A and D). Likewise, trkA
immunoreactivity in oocytes appeared more abundant in oocytes of a
subpopulation of primordial follicles (Fig. 1E) than in oocytes of
follicles in more advanced stages of development (Fig. 1, A and D). A
similar distribution of both p75NTR and trkA
immunoreactive cells was observed in the ovaries from wild-type animals
Fig. 1, A and D) and NGF knockout animals (Fig. 1, B and E).
Ovarian sections incubated in the absence of trkA antibodies showed a
near complete absence of trkA immunoreactive material (Fig. 1C).
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, examples denoted by
arrows), prethecal cells (Fig. 2A, short arrows),
and interstitial cells (Fig. 2, A–C, examples denoted by
arrows in B). Figure 2C provides an example of trkA mRNA
hybridization signal in the oocyte of a follicle with more than two
layers of granulosa cells (black arrow), and Fig. 2D illustrates the presence of trkA mRNA in oocytes of a subpopulation
of primordial follicles (arrows). As was the case of trkA
immunoreactivity, trkA mRNA abundance seemed to be greater in these
small oocytes than in those in a more advanced stage of
development.
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).
Primordial follicles are the initial result of follicular assembly, a
differentiation process in which individual oocytes become surrounded
by a single layer of flattened epithelial pregranulosa cells, which is
in turn separated by a basal lamina from a single layer of elongated
mesenchymal cells that separates the newly formed follicles from one
another (13, 14). Primary follicles are those in which the
epithelial pregranulosa cells surrounding the oocyte have acquired a
cuboidal aspect; they represent the first stage of follicular growth.
Secondary follicles are those containing two or more layers of
pregranulosa cells solidly surrounding the oocyte, with no signs of
antrum formation. Although the ovaries from
NGF+/+ and NGF+/- animals
had extensive regions with an abundance of primary and secondary
follicles (Fig. 3, A and C), the presence of such follicles in
NGF-/- ovaries was only sporadically detected
(Fig. 3, B and D). Instead, NGF-/- ovaries had
a predominance of areas containing tightly packed primordial follicles
intermingled with naked oocytes (Fig. 3D).
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, right). As suggested
by the morphological aspect of the ovary,
NGF-/- ovaries had a normal number of
primordial follicles (Fig. 4, middle), but a significant
increase in the number of naked oocytes (Fig. 4, left),
i.e. those that had failed to be enclosed by somatic cells
into a primordial follicle. Histopathological examination of two other
endocrine glands, the anterior pituitary and the adrenal gland,
performed by the Pathology Laboratory of the Oregon Regional Primate
Research Center (Beaverton, OR), showed no developmental and/or
organizational deficiencies in the cellular structure of these
glands.
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), indicating that the delayed
growth of primordial follicles seen in NGF-/-
mice is not due to a gonadotropin deficiency.
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). Immunohistochemical detection of the
proliferation marker PCNA followed by quantitation of the labeled
nuclei in serial sections demonstrated a substantially reduced
mesenchymal cell proliferation in the ovaries from
NGF-/- mice as compared with
NGF+/+ controls (Fig. 6, B and B1).
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, C and C1). Although the
overall pattern of PCNA and BrdU staining was similar throughout the
ovary, cells near the ovarian surface were only BrdU immunoreactive.
Although this peculiar difference may have a physiological meaning, it
is also possible that the staining is related to the in
vitro method used for BrdU incorporation, which would allow a more
direct exposure of surface cells to the nucleoside than those inside
the gland. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the normal rat ovary, somatic cell proliferation decreases markedly at the time of follicular assembly (28), probably reflecting a switch from a predominantly proliferative condition to the differentiation mode required for the organization of primordial follicles. Although the proliferation rate detected in newborn NGF+/+ ovaries was identical with that previously described for normal neonatal rat ovaries before follicular assembly (28), cell proliferation in NGF-/- ovaries was as low as that seen in normal ovaries at the time of follicular organization (28), indicating that the absence of NGF results in a premature and inappropriately sustained reduction in ovarian mitogenic activity.
The decrease in trkA and NGF mRNA abundance observed in the normal rat ovary at the time of definitive ovarian histogenesis (7) is in keeping with the notion that a temporally restricted reduction in NGF-initiated signals may be a physiological component of the decrease in mitogenic activity that occur in the ovary during this developmental stage. Considering that the mitogenic effects of NGF on several nonneuronal cell types, including cell lines of mesenchymal origin (35, 36), cells of epithelial origin (40), and ovarian thecal cells themselves (41), have been shown to be mediated by trkA receptors, an involvement of these receptors in mediating the facilitatory effect of NGF on somatic cell proliferation of the neonatal ovary appears likely. A role for trkA in NGF-dependent proliferation of ovarian mesenchymal cells is also in harmony with earlier findings showing that, in the peripubertal ovary, trkA is preferentially, if not exclusively, expressed in the thecal compartment of preovulatory ovaries (3). Although such a role is supported by the significant reduction in the number of PCNA-immunopositive cells (which because of their elongated nuclei were considered to be mesenchymal; Ref. 28) observed in NGF-/- ovaries, the results of BrdU labeling suggest that the NGF deficiency may have also affected the epithelial component of the ovary. The proliferation rate detected using BrdU incorporation (which considered both cells with round and elongated nuclei, i.e. epithelial and mesenchymal cells) was similar to that detected by PCNA staining, indicating that both populations were equally affected by the absence of NGF. If granulosa cells of newly formed follicles lack trkA receptors, as is the case of preovulatory follicles (3), the involvement of an intermediate would have to be invoked to explain potential effects of NGF on epithelial (pregranulosa cells) and granulosa cells of the neonatal-infantile ovary. The examination of 7-day-old mouse ovaries by both immunohistofluorescence-confocal microscopy and hybridization histochemistry procedures provided an answer to this question, as both trkA immunoreactivity and trkA mRNA were (surprisingly) detected in granulosa cells, in addition to mesenchymal cells. Interestingly, granulosa cells from primary follicles appeared to have a greater content of trkA immunoreactive material than those of more developed follicles, indicating that granulosa cells are endowed with trkA receptors at the onset of follicular development. These results also imply that the reduction in the number of primary and secondary follicles detected in the ovaries of NGF-/- mice may be, at least in part, due to the loss of an NGF signal directly mediated by trkA receptors expressed in granulosa cells at these earlier phases of follicular development. Whether granulosa cells lose their complement of trkA receptors during formation of the first antral follicles or later in development, and whether the receptor is lost in all or just a subpopulation of developing follicles remains to be defined. Of interest in this context is the finding that granulosa cells of the bovine ovary express trkA receptors regardless of the size of the follicle (41).
The presence of trkA receptors in oocytes and their particular
abundance in oocytes of primordial follicles suggests that oocytes may
represent an additional target for NGF actions. It would not appear
that the main consequence of such actions is to promote the formation
of primordial follicles as previously shown for the c-kit
ligand (42) and the transcription factor Fig-
(43), because only a mild defect in primordial follicle
formation was detected in NGF-deficient mice. The number of naked
oocytes observed in the ovaries from NGF-/-
mice, though significantly greater than that in wild-type ovaries,
represents a very small fraction (1.2%) of the total number of
primordial follicles that were successfully assembled. However, it is
conceivable that one of the actions of NGF on oocytes is to facilitate
the production of some of those as yet unidentified substances
previously shown to promote granulosa cell proliferation
(44).
The reduction in the number of primary follicles, in the face of an almost normal complement of primordial follicles, observed in NGF-null mutants suggests that NGF is important for the initial differentiation of the flattened pregranulosa cells of primordial follicles into the enlarged, cuboidal shape that characterizes these cells in primary follicles (13, 45, 46). As such, NGF would represent the first identified factor controlling this differentiation process that immediately precedes the initiation of follicular growth. Whether NGF works in concert with other factors to bring about this differentiation process is not known, but is probable. NGF-deficient animals also had a reduction in follicles with more than one layer of granulosa cells, suggesting that the neurotrophin may cooperate with GDF-9/c-kit ligand-dependent mechanisms to bring about the initiation and/or progression of pregranulosa cell growth in primary follicles, as proliferation of these cells (assessed by the expression of PCNA) signals the initiation of follicle enlargement (38).
In addition to any direct effect of NGF on granulosa cells, and particularly in view of the loss of mesenchymal proliferative activity observed in NGF-deficient mice, one needs to consider the possibility that additional mechanisms (this time involving the activation of mesenchymal-to-granulosa cell communication pathways) contribute to the process by which NGF might promote the differentiation of primordial into primary follicles, and the growth of primary follicles into follicles with more than one layer of granulosa cells. Such an action would be in keeping with the concept that mesenchymal cells are required for early follicular development (14). Among the potential candidates for this role one may consider growth factors of the TGFß superfamily because TGFßs are produced in ovarian mesenchymal cells, regulate granulosa cell growth and differentiation (47, 48), and at least the expression of one of them (TGFß1) is under direct NGF transcriptional regulatory control (49). Further experimentation is necessary to clarify this issue.
The present study does not inform us as to the potential role of p75NTR in mediating some of the NGF actions around the time of definitive ovarian histogenesis. Mice carrying a null mutation of the p75NTR gene appear to have a normal complement of primordial, primary, and secondary follicles by the end of the first week of postnatal life (Dissen, G. A., C. Romero, K.-F. Lee, and S. R. Ojeda, unpublished data), indicating that p75NTR is not required for early follicle development. Under certain circumstances, activation of p75NTR has been shown to induce apoptosis (50). Whether the reduction in mesenchymal cell proliferation that occurs around the time of folliculogenesis is accompanied by an increase in apoptosis, and whether such a decrease is a p75NTR-dependent event are issues that await resolution.
Together, the present observations are compatible with the broader concept that NGF contributes to the basic processes of proliferation and differentiation that underlie the development of selective nonneural organs, such as the ovary. This notion is strongly supported by the recent demonstration that the thymus of trkA-deficient mice suffers from severe structural and ultrastructural abnormalities, including a reduction in cell density, loss of epithelial cell organization and differentiation, and appearance of cystic structures within the epithelial component of the gland (40). The profound effects of NGF gene ablation on early follicular growth reported in this paper, and the infertility of mice in which NGF actions were postnatally blocked by transgenic expression of NGF antibodies (51) suggests that NGF plays an important role in the developmental regulation of female reproductive function. An ovarian deficiency of the peptide and/or a defect in its actions may contribute to explaining cases of premature ovarian failure caused by the idiopathic depletion of ovarian follicles in humans (52).
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Acknowledgments |
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Footnotes |
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2 A visiting scientist supported by a fellowship from NICHD
(TW/HD00668) and a Fogarty International Training & Research in
Population & Health grant. Current address: Laboratorio de
Bioquimica, Departmento de Ob/Gyn, Hospital Clinico, Universidad de
Chile, Santos Dumont 999, Santiago, Chile.
Received June 29, 2000.
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M. Shiota, T. Tanihiro, Y. Nakagawa, N. Aoki, N. Ishida, K. Miyazaki, A. Ullrich, and H. Miyazaki Protein Tyrosine Phosphatase PTP20 Induces Actin Cytoskeleton Reorganization by Dephosphorylating p190 RhoGAP in Rat Ovarian Granulosa Cells Stimulated with Follicle-Stimulating Hormone Mol. Endocrinol., April 1, 2003; 17(4): 534 - 549. [Abstract] [Full Text] [PDF]
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 B. Dziedzic, V. Prevot, A. Lomniczi, H. Jung, A. Cornea, and S. R. Ojeda Neuron-to-Glia Signaling Mediated by Excitatory Amino Acid Receptors Regulates ErbB Receptor Function in Astroglial Cells of the Neuroendocrine Brain J. Neurosci., February 1, 2003; 23(3): 915 - 926. [Abstract] [Full Text] [PDF]
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S. Mazaud, C. J. Guigon, A. Lozach, N. Coudouel, M. G. Forest, H. Coffigny, and S. Magre Establishment of the Reproductive Function and Transient Fertility of Female Rats Lacking Primordial Follicle Stock after Fetal {gamma}-Irradiation Endocrinology, December 1, 2002; 143(12): 4775 - 4787. [Abstract] [Full Text] [PDF]
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P. S. Hartley, R. A. L. Bayne, L. L. L. Robinson, N. Fulton, and R. A. Anderson Developmental Changes in Expression of Myeloid Cell Leukemia-1 in Human Germ Cells during Oogenesis and Early Folliculogenesis J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3417 - 3427. [Abstract] [Full Text] [PDF]
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C. Romero, A. Paredes, G. A. Dissen, and S. R. Ojeda Nerve Growth Factor Induces the Expression of Functional FSH Receptors in Newly Formed Follicles of the Rat Ovary Endocrinology, April 1, 2002; 143(4): 1485 - 1494. [Abstract] [Full Text] [PDF]
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A. L. L. Durlinger, M. J. G. Gruijters, P. Kramer, B. Karels, H. A. Ingraham, M. W. Nachtigal, J. Th. J. Uilenbroek, J. A. Grootegoed, and A. P. N. Themmen Anti-Mullerian Hormone Inhibits Initiation of Primordial Follicle Growth in the Mouse Ovary Endocrinology, March 1, 2002; 143(3): 1076 - 1084. [Abstract] [Full Text] [PDF]
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D. B. Seifer, B. Feng, R. M. Shelden, S. Chen, and C. F. Dreyfus Brain-Derived Neurotrophic Factor: A Novel Human Ovarian Follicular Protein J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 655 - 659. [Abstract] [Full Text] [PDF]
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R. A. Anderson, L. L. L. Robinson, J. Brooks, and N. Spears Neurotropins and Their Receptors Are Expressed in the Human Fetal Ovary J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 890 - 897. [Abstract] [Full Text] [PDF]
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