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. 2011 Jul;25(7):2256-65.
doi: 10.1096/fj.11-181099. Epub 2011 Mar 16.

Linkage of Regulators of TGF-β Activity in the Fetal Ovary to Polycystic Ovary Syndrome

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Free PMC article

Linkage of Regulators of TGF-β Activity in the Fetal Ovary to Polycystic Ovary Syndrome

Nicholas Hatzirodos et al. FASEB J. .
Free PMC article

Abstract

Although not often discussed, the ovaries of women with polycystic ovary syndrome (PCOS) show all the hallmarks of increased TGF-β activity, with increased amounts of fibrous tissue and collagen in the ovarian capsule or tunica albuginea and ovarian stroma. Recent studies suggest that PCOS could have fetal origins. Genetic studies of PCOS have also found linkage with a microsatellite located in intron 55 of the extracellular matrix protein fibrillin 3. Fibrillins regulate TGF-β bioactivity in tissues by binding latent TGF-β binding proteins. We therefore examined expression of fibrillins 1-3, latent TGF-β binding proteins 1-4, and TGF-β 1-3 in bovine and human fetal ovaries at different stages of gestation and in adult ovaries. We also immunolocalized fibrillins 1 and 3. The results indicate that TGF-β pathways operate during ovarian fetal development, but most important, we show fibrillin 3 is present in the stromal compartments of fetal ovaries and is highly expressed at a critical stage early in developing human and bovine fetal ovaries when stroma is expanding and follicles are forming. These changes in expression of fibrillin 3 in the fetal ovary could lead to a predisposition to develop PCOS in later life.

Figures

Figure 1.
Figure 1.
Expression levels of FBN1 (A), FBN2 (B), FBN3 (C, D), LTBP1 (E), LTBP2 (F), LTBP3 (G), LTBP4 (H), TGFB1 (I), TGFB2 (J), and TGFB3 (K) mRNA in whole fetal human ovary and adult tunica/cortical stroma. A–C, E–K) Data are means ± se (fmol/nmol 18S ribosomal RNA). For analysis, samples were grouped into 3 estimated gestational stages: first trimester (8–11 wk; germ cell proliferation), early second trimester (14–16 wk; some initiation of meiosis), and late second trimester (17–21 wk; widespread meiosis, follicle formation); n = 5–6/group. Data were analyzed by 1-way ANOVA with post hoc Tukey's test. Data for FBN2, FBN3, LTBP1, and LTBP2 were log transformed before analyses. *P < 0.05, **P < 0.01, ***P < 0.001, significant differences. D) Scatter plot of FBN3 expression vs. estimated gestational age.
Figure 2.
Figure 2.
Expression levels of FBN1 (A), FBN2 (B), FBN3 (C, D), LTBP1 (E), LTBP2 (F), LTBP3 (G), LTBP4 (H), TGFB1 (I), TGFB2 (J), and TGFB3 (K) mRNA levels in bovine ovarian tissues. A–C, E–K) Data are means ± se (fmol/nmol 18S ribosomal RNA); n = 8, 11, 9, and 5–8 for whole ovaries from fetuses with crown-rump length of <30, 30–60, and >60 cm (estimated as <125, 125–194, and >194 d of gestation age, respectively, with bovine gestation being 282 d) and adult ovarian tunica/cortex, respectively. Data were analyzed by 1-way ANOVA with post hoc Tukey's test. Data for FBN1, FBN3, LTBP1, LTBP2 were log transformed before analyses. *P < 0.05, **P < 0.01, ***P < 0.001. D) Scatter plot of FBN3 expression levels vs. fetal crown-rump length.
Figure 3.
Figure 3.
Merged images of dual immunolocalization of fibrillin 1 (red in A–C; green in D) and the basal lamina components of laminin 111 (green in A–C; red in D) counterstained with DAPI (blue) in bovine ovaries of fetuses at crown-rump length of 13 (A), 50 (B), 54 (C), and 75 cm (D), estimated as 86, 171, 181, and 229 d of gestation, respectively. Scale bars = 20 μm. Asterisks indicate follicles; diamonds indicate nests of oogonia.
Figure 4.
Figure 4.
A, C, D) Immunolocalization of fibrillin 3 (red) counterstained with DAPI (blue) in bovine ovaries of fetuses of crown-rump length 16 (A), 28 (C), and 50 cm (D), estimated as 93, 120, and 171 d of gestation, respectively. B) Merged images of immunolocalization of fibrillin 3 (red) and Oct 3/4 (green) counterstained with DAPI (blue) in bovine ovary at crown-rump length of 11.5 cm, estimated as 82 d of gestation. Scale bars = 50 μm (A, C, D); 25 μm (B).
Figure 5.
Figure 5.
Immunolocalization of fibrillin-3 (red) counterstained with DAPI (blue) in human ovaries at 10 (A), 12 (B), 14 (C), and 19 (D) wk of gestation and in fetal lung at 18 wk of gestation (E). Scale bars = 50 μm (A–D); 25 μm (E). Asterisks indicate terminal bronchioles. m, medulla; c, cortex.

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