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RESEARCH |
Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, WA 99164-4231, USA
Correspondence should be addressed to M K Skinner; Email: skinner{at}wsu.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Several paracrine growth factors have been shown to act locally within the ovary to regulate the primordial to primary follicle transition. Bone morphogenetic protein 15 (BMP15), basic fibroblast growth factor (bFGF/FGF2), the neurotrophins NT4 and bone-derived neurotropic factor (BDNF), the c-kit receptor for kit ligand (KITL) and the Trk-B receptor for NT4 and BDNFare all present in the oocytes of primordial follicles. All these growth factors and receptors have been implicated in promoting the primordial to primary follicle transition (Manova et al. 1990, Horie et al. 1991, van Wezel et al. 1995, Dube et al. 1998, Laitinen et al. 1998, Parrott & Skinner 1999, Nilsson et al. 2001, Paredes et al. 2004). Several growth factors found to be present in the pre-granulosa cells surrounding primordial follicles or in granulosa cells were also found to promote the primordial to primary follicle transition including KITL and leukemia inhibitory factor (LIF) (Manova et al. 1993, Motro & Bernstein 1993, van Wezel et al. 1995, Yamamoto et al. 1997, Parrott & Skinner 1999, Nilsson et al. 2001). The thecal/interstitial cells surrounding follicles express bone morphogenetic protein 4 (BMP4) and BMP7, both of which promote the primordial to primary follicle transition. BMP4 has also been shown to be important for follicle survival (Lee et al. 2001, Nilsson & Skinner 2003). Anti-Müllerian hormone/Müllerian inhibitory substance (AMH/MIS) is a growth factor produced by the granulosa cells of developing pre-antral and antral follicles which inhibits the primordial to primary follicle transition (Baarends et al. 1995, Durlinger et al. 1999, 2002).
Platelet-derived growth factor (PDGF), neuregulin (NRG) and vascular endothelial growth factor (VEGF) were all identified as candidate signaling factors toregulate the primordial to primary follicle transition with a microarray analysis previously performed (Kezele et al. 2005b). These factors change mRNA expression levels during primordial to primary follicle transition, suggesting that they may regulate early follicle development (Kezele et al. 2005b). The present study was designed to investigate the potential regulatory roles of PDGF, VEGF and NRG in primordial to primary follicle transition.
The most prevalent isoforms of PDGF are the PDGF-AA, PDGF-BB homodimers, and PDGF-AB heterodimers. PDGF-AA, PDGF-AB and PDGF-BB bind to the PDGF receptor-alpha (PDGFR
), while the PDGFRß binds primarily PDGF-BB. After binding and activation of the monomeric and ß receptors, these receptors dimerize and activate various intracellular signaling kinase cascades (Fredriksson et al. 2004, Tallquist & Kazlauskas 2004). PDGF receptors have been shown to be present in the theca and stroma compartments of porcine ovaries (Taylor 2000). PDGF has been demonstrated to affect the proliferation or function of both theca cells (Duleba et al. 1999, Shores & Hunter 2000, Taylor 2000) and granulosa cells (Hammond et al. 1985, Anderson & Lee 1993, Lafrance et al. 1993), as well as ovarian surface epithelium (Dabrow et al. 1998). No studies have been reported that examine any effect PDGF may have on the early stages of follicle development.
NRGs are the protein products of a family of related genes. The NRG1 gene is the one for which the most biological functions are known. The NRG1 gene produces several alternatively spliced proteins, some of which are transmembrane proteins with an extracellular domain. This extracellular domain can be cleaved off to release paracrine signaling molecules (Falls 2003). NRGs bind to the Erbß receptors, with NRG1 binding to Erbß2, Erbß3 and Erbß4 (Falls 2003). NRG1-ß is involved in colonization of the genital ridge with primordial germ cells (Kierszenbaum & Tres 2001), while NRG1- and NRG1-ß are both implicated in growth of ovarian cancer cells.
VEGF is a well-characterized growth factor that binds to receptors VEGFR1 and VEGFR2. VEGF is best known as a stimulator of angiogenesis. It is in this role that VEGF has been shown to act in the ovary by stimulating vascular development in the theca layer of pre-antral and antral follicles and stimulating follicle growth (Zimmermann et al. 2003, Hunter et al. 2004, Iijima et al. 2005).
The objective of the present study was to investigate what role PDGF, NRG and VEGF may play in the primordial to primary follicle transition. The effect of these growth factors on the primordial follicle transition was examined using a rat ovary organ culture system. The ability of the growth factors to regulate expression of KITL, a known stimulator of primordial follicle development (Parrott & Skinner 1999), was also examined. A better understanding of the factors that regulate the primordial to primary follicle transition can lead to treatments for some infertilities such as premature ovarian failure.
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Materials and Methods |
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Morphological evaluation
Four-day-old rat ovaries were fixed fresh or cultured for 2 weeks and then fixed in Bouin’s solution (0.9% picric acid, 9% formaldehyde, 5% acetic acid) for 1–2 h. Ovaries were paraffin embedded and sectioned at 3–5 µm. Ovaries were de-paraffinized in xylenes and hydrated through an ethanol series. Sections were stained with hematoxylin and eosin using standard protocols. The number of follicles at each developmental stage was counted in two serial sections and averaged from the largest cross-sections through the center of the ovary. The oocyte nucleus had to be visible in a follicle in order for the follicle to be counted. Normally, 100–200 follicles were present in a cross-section. Previously, it has been demonstrated that the total follicle number per section does not change after 2 weeks of culture compared to freshly isolated 4-day-old ovaries (Parrott & Skinner 1999). Follicles were classified as either primordial (stage 0), or as one of the developing pre-antral stages (stages 1–4) as described previously (Parrott & Skinner 1999). Briefly, primordial follicles consist of an oocyte partially or completely encapsulated by squamous pre-granulosa cells. Developing (stages 1–4) follicles contain successively more cuboidal granulosa cells in layers around the oocyte (Parrott & Skinner 1999, Nilsson et al. 2001). The results of follicle counting are presented as percentages (%primordial vs %developing) to account for differences between individual mice in total number of oocytes per section.
Immunohistochemistry
Localization of PDGF protein was determined by immunohistochemical analysis. Rat ovaries were fixed and prepared for immunostaining as for H&E staining as described above. Antigens were exposed by boiling sections for 5 min in 0.01 M sodium citrate buffer at pH 6.0. A solution of 10% goat serum in PBS was used as a blocking agent prior to incubating sections with primary antibody overnight at 4 °C. Slides were incubated with polyclonal rabbit anti-human PDGFantibody (Santa Cruz Biotechnology, Inc.; Santa Cruz, CA) at 10 µg/ml overnight at 4 °C. Secondary antibody (biotinylated goat anti-rabbit IgG, Vector, Burlingame, CA, USA) was detected by using the Vectastain kit (Vector) and diaminobenzadine (Vector). Negative controls were incubated in the presence of non-immune rabbit IgG as a primary antibody at 10 µg/ml.
Real-time PCR
Ovaries were isolated from 4-day-old rats and placed into culture as described above. Cultured ovaries were treated for 2 days with recombinant rat PDGF-AB heterodimer (R&D Systems) at 50 ng/ml, or rat KITL (Amgen) at 50 ng/ml, or were left untreated as controls. Three ovaries from the same culture well were pooled to make each RNA sample. RNA was extracted using the Trizol reagent (Sigma). RNA samples were DNAse treated using the TURBO-DNA-free kit (Ambion, Austin, TX). Two micrograms total RNA from each sample was reverse transcribed to cDNA using a standard oligo-dT RT protocol in a reaction volume of 25 µl. cDNA samples were diluted 1:10 and 2 µl of diluted sample/well was used as template for real-time PCR analysis. Each sample was run in triplicate. The Platinum SYBR Green qPCR Supermix kit (Invitrogen) was used according to manufacturers instructions. The KITL primers were rKL-720, 5'ATTTATGTTACCCCCTGTT-GCAGCC3' and rKL-859, 5'CAATTACAAGCGAAATGA-GAGCCG3'. The ribosomal protein gene S2 was used as a references standard for real-time PCR. The S2 reference gene primers were rS2-F, 5'CTGCTCCTGTGCCCAA-GAAG3' and rS2-R, 5'AAGGTGGCCTTGGCAA-AGTT3'. Ribosomal S2 mRNA expression does not change in ovarian cells treated with hormones (Kezele et al. 2005a). Real-time PCR was performed on an ABI-7000 real-time machine with the following protocol: 60 °C 2 min, 95 °C 10 min, then 40 cycles of 95 °C 20 s and 68 °C 90 s. Fluorescent detection data were analyzed such that KITL product levels were normalized to S2 gene levels, and then PDGF- and KITL-treated sample KITL levels were normalized to untreated control KITL levels.
Microarray analysis
RNA was hybridized to the Affymetrix (Affymetrix; Santa Clara, CA) rat 230 2.0 gene chip. The Genomics Core in the Center for Reproductive Biology at Washington State University performed the analysis as previously described (McLean et al. 2002, Shima et al. 2004). Briefly, RNA from control and KITL-treated (50 ng/ml for 2 days as described above) whole cultured ovaries was reverse transcribed into cDNA and cDNA was transcribed into biotin labeled RNA. Biotin labeled RNA was then hybridized to the Affymetrix 230 2.3 gene chips. Each gene set is composed of 16 pairs of 24-mer oligonucleotides, with one sense strand specific for the gene and one anti-sense strand with single point mutations for use as comparative negative control. The oligonucleotides span the gene so 5' and 3' regions are contributing to the final signal obtained. Biotinylated RNA was then visualized by labeling with phycoerythrin-coupled avidin. The microarray was scanned on a Hewlett-Packard Gene Array Scanner (Hewlett-Packard Co.; Palo Alto, CA, USA). Two microarray chips from two different RNA samples were analyzed for each of the control and KITL-treated ovary preparations.
Bioinformatics
Microarray output was examined visually for excessive background noise and physical anomalies. GCOS software (Affymetrix) was used for analyses. An absolute analysis using GCOS was performed to assess the relative abundance of the transcripts based on signal and detection (present, absent, or marginal) for the 16 different oligonucleotides per gene and comparison for analysis. The absolute analysis from GCOS was imported into GeneSpring 7.0 software (Silicon Genetics; Redwood City, CA). The data were normalized within GeneSpring using the default/recommended normalization methods. These include setting of signal values below 0.01–0.01, total chip normalization to the 50th percentile, and normalization of each gene to the median. These normalizations allowed for the visualization of data based on relative abundance at any given time point rather than compared to a specific control value. Means of the raw signal values for control or KITL-treated replicate gene arrays were used to determine expression or change in expression of mRNA for selected genes. Previous studies have shown that microarray data correlate well with real-time quantitative PCR and Northern analysis (McLean et al. 2002, Sadate-Ngatchou et al. 2004).
Statistics
Pair comparisons were performed using Student’s t-test. Multiple comparison tests were performed using Dunnet’s analysis after a significant difference had been found with ANOVA. Dunnet’s test compares each treatment group to the designated control group. In the case of real-time PCR data, in which all values are normalized so that controls are equal to 1, a one-sample t-test was performed to test if the means differ significantly from 1.0. Groups were considered significantly different if P
0.05. All statistics were calculated with the help of GraphPad Prism version 3.0a for Macintosh, GraphPad Software (San Diego, CA, USA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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The total number of combined primordial and developing follicles per ovary cross-section was 151±10 for controls, 116±9 for PDGF-treated ovaries, 130±13 for anti-PDGF treated ovaries, and 114±2 for KITL-treated ovaries. Approximately, 1500 follicles per treatment were counted for this study. These total ovary counts are not significantly different (using an ANOVA analysis) between treatment groups, indicating that no treatments result in a loss or gain in follicles compared to controls. These results are similar to those found by Parrott & Skinner (1999). Treatments can result in a change in the relative proportion of primordial and developing follicles. PDGF-treatment resulted in a significant (P<0.05) increase in the percentage of developing follicles compared to the percentage of developing follicles in controls (Fig. 1
). This is necessarily accompanied by a concomitant decrease in the percentage of primordial follicles compared to that of controls. Observations indicate an increase in the rate of primordial to primary follicle transition. Conversely, ovaries treated with anti-PDGF neutralizing antibody were found to have a significant (P<0.05) decrease in primary follicles indicating a decrease in primordial to primary follicle transition compared to controls. KITL is known to stimulate primordial to primary follicle transition (Parrott & Skinner 1999) and was used as a positive control for the organ culture system. KITL-treatment resulted in a significant (P<0.05) increase in the proportion of primary follicles indicating an increase in primordial to primary follicle transition (Fig. 1).
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). From examination of staining intensity, it is possible that PDGF protein expression is higher in the oocytes of developing rather than primordial follicles. However, one cannot exclude the possibility that differences in fixation or handling of ovaries resulted in these staining differences. There was negligible staining in the surrounding somatic cells (Fig. 3).
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). These results suggest that mRNA collected from ovaries after 2 days of treatment with growth factors would reflect changes in gene expression due to the treatment, without reflecting changes in gene expression due to a different population of follicles and differentiated cells.
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). RNA was also isolated from ovaries cultured for 2 days with or without KITL-treatment (50 ng/ml) and that RNA used for microarray analysis using the Affymetrix 230 2.0 rat chip. Selected genes related to PDGF and PDGF receptors were analyzed. No change in mRNA levels were seen between control and KITL-treated ovaries for PDGFa, PDGFb, PDGFc, PDGFd, PDGF receptor alpha (PDGFRa), PDGF receptor beta (PDGFRb), or PDGFa-associated protein 1 (Table 1). Therefore, PDGF was found to stimulate expression of KITL mRNA, but KITL had no effect on PDGF or PDGF receptor expression. KITL-treatment had no effect on expression of NRG1, the NRG receptor signaling pathway protein Tob2, VEGFa isoform or VEGF receptor (Table 1). KITL-treatment did stimulate the expression of mRNA for the NRG receptor signaling pathway protein Tob1 and the VEGFc isoform (Table 1). As previously reported, the microarray data have been validated with an alternate procedure involving quantitative PCR analysis (Kezele et al. 2005b).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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). It is not surprising that a process so vital to reproduction is regulated by multiple factors and may feature redundancy.
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). Neither NRG1 nor VEGF were shown to promote primordial to primary follicle transition, even though mRNA expression of these genes has been shown to change during follicle transition (Kezele et al. 2005b). This suggests that these growth factors are either involved in some signaling process other than promoting primordial follicle transition, or that they require as yet unknown cofactors to affect follicle transition. VEGF protein expression has been demonstrated in developing primary, but not primordial follicle oocytes (Celik-Ozenci et al. 2003). Further investigations will be needed to determine the role these growth factors play in early follicle development.
The results from the present experiments indicate that PDGF can join the growing list of extracellular signaling factors that regulate the primordial to primary follicle transition. The actions of some of these factors are summarized in Fig. 6. KITL from granulosa cells acts on the oocyte and also upon the surrounding stroma to recruit theca cells (Parrott & Skinner 1999, Parrott & Skinner 2000). Theca/interstitial cells produce BMP4, which acts as a follicle survival factor (Nilsson & Skinner 2003). KGF, also from the theca, acts on granulosa cells to promote KITL expression and follicle development (Kezele et al. 2005a). Granulosa cells produce LIF that acts on the oocyte as well as on other granulosa cells (Nilsson et al. 2002). Insulin acts in an endocrine manner on the oocyte (Kezele et al. 2002b). AMH/MIS from larger growing follicles acts to inhibit the primordial to primary follicle transition (Baarends et al. 1995, Durlinger et al. 1999, Durlinger et al. 2001). The oocyte produces bFGF that acts upon the granulosa and theca cells (Nilsson et al. 2001). Similar to PDGF, bFGF also stimulates KITL expression to facilitate primordial follicle development (Nilsson & Skinner 2004). In this study, it is proposed that the oocyte produces PDGF, which acts upon surrounding granulosa and theca/interstitial cells to promote primordial follicle transition (Fig. 6). In summary, a network of compensatory cell–cell interactions involving multiple growth factors is required to modulate the rate of primordial follicle transition and subsequent follicular growth. A more complete understanding of the molecular and cellular control of primordial follicle development will provide insights into potential new therapeutic targets to treat certain types of infertility or to control the transition to menopause in women.
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Footnotes |
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