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Biology of Reproduction 63, 457-461 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Regular article

Interaction of Extracellular Matrix and Activin-A in the Initiation of Follicle Growth in the Mouse Ovary1

Kutluk Oktay2,,a,b, Guvenç Karlikayab, Orhan Akmanb, George K. Ojakianb, and Maja Oktay3,c

a Departments of Obstetrics & Gynecology, Cornell University, Weill Medical College and New York Methodist Hospital, Brooklyn, New York 11215-9008 b Department of Anatomy & Cell Biology, State University of New York HSC, Brooklyn, New York 11203 c Memorial Sloan-Kettering Cancer Center Research Laboratories, New York, New York 10021

ABSTRACT

The precise mechanism for the initiation of follicle growth and progression through the earliest stages of follicle development remains largely unknown. Activins play a role during early follicle development, and evidence suggests that the extracellular matrix plays a role during later stages of follicular growth. We investigated the role of activin-A and extracellular matrix in follicle growth initiation and early follicular development in the mouse ovary. Ovaries were collected from 5-day-old mice and cultured for 10 days on polylysine, collagen, or laminin in the presence or absence of recombinant human activin-A. Follicle density, indices of follicle growth initiation (primary:primordial follicle [PY:PD] and primary:total follicle [PY:TF] ratios), ratios of multilayer follicle:total follicle (ML:TF), and follicle growth rates were compared between groups. Follicle densities were significantly higher in the extracellular matrix treatment group compared with the polylysine group (P < 0.01). Also, compared with polylysine, both collagen and laminin significantly increased indices of follicle growth initiation (PY:PD ratio: P < 0.001, odds ratio of 3.3; PY:TF ratio: P < 0.001, odds ratio of 2.5), and these were not altered by activin treatment. In the absence of activin-A, exposure to neither collagen nor laminin had an effect on multilayer follicle development. When activin-A was added, collagen and laminin had opposing effects on multilayer follicle development. Activin-A stimulated multilayer follicle development in the presence of laminin (ML:TF ratio: P = 0.01, odds ratio of 10.8), whereas it suppressed follicle growth in collagen (P = 0.01). Activin-A did not affect the ML:TF ratio in the polylysine-treated groups. These results strongly suggest that extracellular matrix components and activin-A interact with each other, and that they regulate follicle growth initiation and multilayer follicle development.

activin, follicle, follicular development, FSH

INTRODUCTION

Primordial follicles form the stockpile of resting follicles from which fractions of follicles are recruited throughout reproductive life [1]. The onset of growth by an individual follicle is unpredictable, with some beginning shortly after formation but others waiting for as long as 50 yr. Of the several hundred thousands of primordial follicles at puberty, only 400–500 will reach the ovulatory stage in a woman's life time, whereas 99.9% will be lost during the lengthy process of follicle development [2]. Factors that govern the initiation of growth initiation and the eventual consumption of the primordial follicle reserve are unknown. Gonadotropins have no effect on follicle growth initiation, both because primordial follicles lack FSH receptors [3] and because follicle growth initiation continues unhampered in hypogonadal states [4–6].

The extracellular matrix (ECM) exerts stringent control on cell proliferation, either by inducing specific signals via integrins or by modifying cell responsiveness to growth factors and hormones [7]. Integrins belong to a widely expressed family of cell surface adhesion receptors [8]. In vertebrates, cell adhesion to ECM is mediated by at least 15 {alpha} and 8 ß subunits, which can variously combine to form 22 receptors, each of which is characterized by a distinct though overlapping ligand-binding specificity. On binding to ECMs such as laminin, collagen, or fibronectin, integrins undergo a conformational change and interact with cytoskeletal elements. This change in conformation results in the organization of cytoskeleton and the formation of focal adhesions [9]. In addition, ligand binding initiates distinct intracellular signals that regulate cell cycle progression, cell survival, and cell differentiation [10, 11]. Growth factors that are ligands of tyrosine-kinase-type receptors co-operate with integrin-signaling pathways. To our knowledge, however, no such interaction with serine-threonine-kinase-type receptors (i.e., activins and transforming growth factor [TGF]-B) has been reported.

Activins are homodimers (ßAßA, ßBßB) or heterodimers (ßAßB) of the ß subunits of inhibin. Hormones of the inhibin/activin family were originally described as being gonadally produced regulators of pituitary hormone release, but they are now known to have a broader range of effects both within and outside the reproductive system [12]. Activins act, in a number of tissues, as a mitogen and a morphogen. They also have significant paracrine and autocrine regulatory effects within the pituitary, ovary, placenta, prostate ,and testis [12]. Activins can enhance both induction and down-regulation of FSH receptors by FSH [13], and they can induce FSH receptors in granulosa cells in the absence of FSH [13, 14]. During the early stages of follicular growth, when FSH responsiveness is not well established, activins may induce FSH receptor expression [12].

Based on existing data regarding the effects of ECM and activin-A (ßAßA) on cell proliferation and differentiation, we hypothesized that ECM and activin-A play a role in follicle growth initiation and early follicle development in the mouse.

MATERIALS AND METHODS

This study was approved by the Institutional Animal Care and Use Committee. Ovaries were obtained from 5-day-old B6D2F1 mice (Taconic Farms, Germantown, NY). At this age, more than 90% of the follicles are still at the primordial stage in the mouse ovary.

Forty ovaries were obtained from 20 animals and were randomly allocated to each treatment group. Four ovaries were fixed and serially sectioned for baseline counts. To confirm that most of the follicles were in primordial state, baseline measurements were obtained by counting follicles in every 40th section. The remaining ovaries were used for organ culture.

Duplicate culture inserts were coated with either polylysine (negative control), collagen type IV, or laminin. The polylysine and collagen type IV were obtained from Sigma Chemical Co. (St. Louis, MO); the laminin was obtained from Gibco (Gaithersburg, MD). Coating was performed by incubating the culture inserts in 20 µg/ml of laminin, collagen type IV, or polylysine for 2 h at room temperature. These inserts were then incubated with 0.2% BSA (Sigma) for 1 h. Ovarian explants were cultured in groups of six for 10 days in Waymouth media (Sigma), which was supplemented with 20% fetal bovine serum, 100 ng/ml of recombinant FSH (provided by A.F. Parlow, NIDDK), 10 ng/ml of epidermal growth factor (EGF), and 10 ng/ml of fibroblast growth factor (FGF). Both EGF and FGF were obtained from Intergen (Purchase, NY). In addition, 100 ng/ml of recombinant human activin-A (provided by A.F. Parlow, NIDDK) was added to one of the two collagen type IV-, laminin-, or polylysine-coated wells (Corning Costar, Cambridge, MA). Media were refreshed every other day. Collagen and laminin were added to media on alternate days at concentrations of 10 µg/ml.

After 10 days of organ culture, tissues were embedded in LR-White resin (Electron Microscopy Sciences, Ft. Washington, PA) and serially sectioned with a glass knife at a thickness of 1 µm. Every 40th section was evaluated for follicle density, and the ratios of primary to primordial follicles (PY:PD, growth initiation index), primary to total follicles (PY:TF), and multilayer to total follicles (ML:TF) were calculated. The results were obtained by averaging counts from all six ovaries in each treatment group.

To determine the follicle density, we reviewed 4–13 sections in each treatment group and counted the total number of follicles in one high-power field (hpf; x100) within each section. The results were averaged and presented as "total number of follicles/hpf." The number of follicles counted in each stage, follicle densities, and growth rates are shown in Table 1.


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  		TABLE 1. Percentage of follicles in each stage, follicle density, and growth rates in baseline (BL) and ECM treatment groups with (A+) or without (A-) activin treatment

On average, 33.6 ± 6.7 sections were evaluated (range, 15–64) in each treatment group. On average, 195.6 ± 31 (range, 104–3120), 44.8 ± 5.6 (range, 26–60), and 20.7 ± 5.7 (range, 2–43) follicles were counted in the primordial, primary, and multilayer categories, respectively. As evident from the mean follicle densities in each treatment group, section-to-section variation in follicle density was not large (Table 1).

A follicle is classified as being primordial if all the granulosa cells are flattened; if one or more granulosa cells have become cuboidal, it is considered to be at the primary stage. Follicles with partial or complete doubling of the granulosa cell layer are classified as being multilayered. Follicle growth rate is defined as being the percentage of the primary and multilayer follicles among all follicles.

Statistical Analysis

To determine the interaction between activin and ECM in primordial follicle growth initiation, a two-way ANOVA was performed. A logistic regression analysis was performed to calculate the odds ratios for each ECM, with or without activin treatment, and growth ratios were compared with contingency tables. When post-hoc comparisons were made, Bonferroni correction was applied. A P value of less than or equal to 0.05 was considered to be significant.

RESULTS

Ovarian tissues cultured on polylysine, laminin, and collagen had significantly higher follicle growth rates and lower follicle densities after 10 days of culture (Table 1) compared with baseline (P = 0.001). Compared with polylysine, however, follicle densities were significantly higher in the ECM treatment groups (9.2 ± 0.6 follicles/hpf vs. 5.9 ± 0.4 follicles/hpf, P < 0.001). At post-hoc analysis, only laminin had a significant effect on follicle density (P < 0.001), but the effect of collagen approached significance (P = 0.06). Administration of activin-A did not affect follicle density.

Compared with polylysine, both collagen and laminin resulted in significantly higher PY:PD (P < 0.001, odds ratio of 3.3) and PY:TF ratios (P < 0.001, odds ratio of 2.5; Fig. 1A). Again, activin-A treatment did not influence these indices.



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  		FIG. 1. Effects of ECM and activin-A on early follicle development. A) ECM stimulates follicle growth initiation (PY:PD ratio) regardless of type and activin treatment. aP < 0.001. B) ECM interacts with activin-A so that collagen suppresses and laminin enhances multilayer follicle development (ML:TF ratio). In the absence of activin-A, ECM has no effect on multilayer follicle development. Lower-case letters indicate significant (P < 0.01) differences between the groups with the same letters. C, Collagen type IV; L, laminin; PL, polylysine

When collagen or laminin groups were compared with the polylysine group, no difference in multilayer follicle development (ML:TF ratio) was observed (Fig. 1B). However, two-way ANOVA revealed a profound effect of activin on multilayer follicle development, which was apparent only if the ovarian tissue was cultured on ECM (collagen or laminin). In the presence of laminin, activin-A enhanced the ML:TF ratio (P = 0.004). In contrast, in the presence of collagen, activin-A suppressed multilayer follicle development (P = 0.01; Fig. 1B). Stating it differently, in activin-A-supplemented media, a follicle was 10.8-fold more likely (odds ratio) to reach the multilayer stage on laminin compared with collagen.

Morphologically, follicles in tissues cultured on polylysine appeared to be disorganized and the follicle structure loosely preserved, regardless of activin treatment (Fig. 2, A and B). In contrast, regardless of whether activin was added or not, follicle morphology was similar to controls in all ECM treatment groups (Fig. 2, C–J).



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  		FIG. 2. Histological sections of ovaries cultured on polylysine (PL), collagen (C), and laminin (L). A) PL with activin-A. Most of the follicles are in the primordial stage, and their structure appears to be less organized. Bar = 50 µm, x40. B) PL with activin-A at higher magnification. Occasional primary follicles (arrow) can be seen. The findings in tissues treated with PL alone are essentially the same (not illustrated). Bar = 20 µm, x100. C) Collagen type IV without activin-A. Note the cluster of primary follicles (arrows). Bar = 50 µm, x40. D) Multiple primary follicles in collagen type IV without activin-A (arrow). Bar = 20 µm, x100. E) Collagen type IV with activin-A. Primordial and primary follicles (flanked by arrows), but no multilayer follicles, are seen. Bar = 50 µm, x40. F) Collagen with activin-A. Note the multiple primary follicles (arrows). Bar = 20 µm, x100. G) L without activin-A. Note the similar proportion of follicles in the primary stage (arrows) compared to that with collagen type IV with or without activin-A. Bar = 50 µm, x40. H) L without activin-A. Note the increased ratio of primary follicles (black arrows) compared to primordial ones (white arrow). Bar = 20 µm, x100. I) L with activin-A. Note the array of follicles ranging from primordial (white arrow) to primary (spearhead) and multilayer (white arrows). Also note the continuum of follicle stages from left to right. Bar = 50 µm, x40. J) L with activin-A. Several multilayer follicles are grouped together. Bar = 20 µm, x100

An interesting observation in the laminin + activin group was the tendency of progressive follicle stages to be in continuum with each other (Fig. 2, I and J). In many sections, a cluster of primordial follicles was adjacent to primary-stage follicles, which, in turn, neighbored multilayer-stage follicles.

DISCUSSION

In this article, we present evidence for a role of ECM and activin-A during the early stages of follicle development in the mouse ovary. We found that the transition from primordial to primary stage depends on both collagen and laminin, but not on activin-A. Transition from primary to multilayer stage was enhanced by an interaction between laminin and activin-A but suppressed by an interaction between collagen and activin. To our knowledge, this is the first time that evidence for a mechanism involving ECM-activin interaction has been presented for follicle growth initiation.

The ovary is in a constant remodeling state, because many follicles are growing, dying, or ovulating continually. As a result, ovarian follicular cells make and break adhesions with the ECM and, thus, can stimulate different integrin-signaling pathways and modify their response to locally secreted growth factors as well as endocrine hormones. A study in the mouse showed that gonadotropin responsiveness was altered in multilayer follicles when the animals were treated with anti-integrin {alpha}6 antibodies [15]. Interestingly, the {alpha}6 subunit is a component of several laminin receptors.

In the marmoset ovary, follicle atresia is associated with diminished expression of the integrin subunits ß1 and {alpha}6 [16]. Moreover, granulosa cells secrete various components of ECM, and this secretion is influenced by gonadotropins [17]. Both FSH and insulin decrease, whereas GnRH increases, fibronectin production from rodent granulosa cells. In addition, granulosa cells from preantral follicles secrete considerably larger amounts of fibronectin than granulosa cells from antral follicles [18].

Collagen type IV, laminin, and heparan sulfate proteoglycans are present in the basement membrane of the rodent ovarian follicles [19–21]. Interestingly, immunoelectron microscopic studies of rat ovaries have shown that laminin is absent from the primordial follicles but is detected in the preantral and antral follicles [22]. These earlier findings are in accordance with our own that laminin and other ECM components are essential in the process of follicle growth initiation.

The importance of the TGF-ß superfamily of dimeric proteins in ovarian follicle development has been shown in many studies. Mice deficient in ActRcII (i.e., type-II activin receptor) lack a normal estrous cycle, and their ovaries show increased atresia [23]. Even stronger evidence supports a role for the more recently discovered members of the TGF-ß family in follicle growth initiation. In female mice that are null for the oocyte-specific growth differentiation factor (GDF)-9, follicle growth does not progress to the multilayer stages [24]. Granulosa cells from GDF-9-deficient follicles fail to proliferate but also to undergo cell death [25]. Growth of preantral follicles isolated from immature rats is enhanced by treatment with either GDF-9 or FSH, and combined treatment shows an additive effect [26]. Finally, bone morphogenic protein-15 shares a coincident expression with the mouse GDF-9, and it likely is an influential factor in follicle growth initiation [27]. None of these studies, however, examined the role of ECM in the initiation of follicular growth or the interaction with TGF-ß family ligands.

The concept that normal cells require adhesion to ECM to respond to growth factors is well established. Various studies from different groups have supported the model in which integrins co-operate with growth factor receptors to produce a synergistic stimulation of one or more mitogenic signaling pathways [28–30]. In addition, recent data suggest that integrins activate a distinct signaling pathway, which is not significantly activated by growth factors but is necessary for cell proliferation [10]. Yet, certain integrins associate preferentially with specific growth factor receptors and, thus, contribute to their activation [31].

Although integrin signaling interacts only with tyrosine-kinase-receptor signaling pathways [32, 33], herein we suggest a novel interaction between serine-threonine-kinase-type receptor pathways (e.g., receptors for the TGF-ß family ligands) and integrins in the regulation of cell proliferation. Further studies are needed, however, to explain the mechanism of interaction between ECM and activin by which laminin enhances and collagen suppresses cell proliferation.

ACKNOWLEDGMENTS

We thank Dr. A.F. Parlow from NIDDK's NHPP for kindly providing the FSH and activin. We also thank Wei Quan for tissue-sectioning.

FOOTNOTES

First decision: 22 December 1999.

1 Supported by the ASRM-Mead Johnson and ASRM-Serono Research Grants. Back

2 Correspondence: Kutluk Oktay, Department of Obstetrics & Gynecology, Cornell University, Weill Medical College and New York Methodist Hospital, 506 Sixth Street, Brooklyn, NY 11215-9008. FAX: 718 780 3079; koktay{at}netmail.hscbklyn.edu Back

3 Current address: Department of Pathology, Yale University Medical School, New Haven, CT. Back

Accepted: March 17, 2000.

Received: November 22, 1999.

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