Smad 3 regulates proliferation of the mouse ovarian surface epithelium

Symonds, Daniel A.; Tomic, Dragana; Borgeest, Christina; McGee, Elizabeth A.; Flaws, Jodi A.

doi:10.1002/ar.a.10090

Cited by 17 publications

(15 citation statements)

References 24 publications

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“…The siRNA study also demonstrated an important role for Smad3 in ER expression. Consistent with our results, in a study investigating involvement of Smad3 in ovarian surface epithelium (OSE) proliferation, it was shown that ER␣ expression is dramatically decreased in OSE of Smad3 homozygous knock-out mice compared with wild type mice (74). Smad3 can bind to DNA directly, and an 8-bp palindromic sequence 5Ј-GTCTAGAC-3Ј has been identified as a Smad binding element for the highly conserved MH1 domain of human Smad3 and -4 (73).…”

Section: Discussionsupporting

confidence: 79%

Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary

Kipp

Kilen

Woodruff

et al. 2007

Journal of Biological Chemistry

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Activin, a member of the transforming growth factor-␤ superfamily, is an important modulator of follicle-stimulating hormone synthesis and secretion in the pituitary and plays autocrine/paracrine roles in the regulation of ovarian follicle development. From a microarray study on mouse ovarian granulosa cells, we discovered that the estrogen receptor ␤ (ER␤) is inducible by activin. We previously demonstrated that estrogen suppresses activin gene expression, suggesting a feedback relationship between these two follicle-regulating hormones. The purpose of this study was to investigate fully activin A regulation of ER expression. Real time reverse transcription-PCR assays on cultured granulosa cells showed that both ER␣ and ER␤ mRNAs were induced by activin A at 4, 12, and 24 h in a dose-responsive manner. Western blots confirmed an increase in their protein levels. Consistent with increased ER␣ and ER␤ expression, activin A stimulated estradiol-induced estrogen response element promoter activity. Activin A stimulation of ER expression was a direct effect at the level of gene transcription, as it was not abolished by cycloheximide but was abolished by actinomycin D, and in transfected granulosa cells activin A stimulated ER␣ promoter activity. To investigate the effect of activin in vivo and, thus, its biological significance, we examined ER expression in inhibin transgenic mice that have decreased activin expression and discovered that these mice had decreased ER␣ and ER␤ expression in the ovary. We also found that ER mRNA levels were decreased in Mü llerian inhibiting substance promoter (MIS)-Smad2 dominant negative mice that have impaired activin signaling through Smad2, and small interfering RNAs targeting Smad2 or Smad3 suppressed ER␣ promoter activation, suggesting that Smad2 and Smad3 are involved in regulating ER levels. Therefore, this study reveals an important role for activin in inducing the expression of ERs in the mouse ovary and suggests important interplay between activin and estrogen signaling.Activin and its functional antagonist inhibin were originally isolated from gonadal sources as endocrine factors regulating the synthesis and secretion of follicle-stimulating hormone by the pituitary gland (1-8). More recent studies have indicated that activin acts predominantly as a local paracrine and autocrine factor (9, 10). Consistent with the fact that activin is a member of the transforming growth factor-␤ (TGF-␤) 2 superfamily, activin has a variety of functions and is involved in many physiological processes, including embryonic development, wound repair, inflammation, renal tubule morphogenesis, and neuroprotection. In the reproductive system, in addition to regulating gonadotropin release, activin and inhibin have been shown to play an important role in regulating the formation and development of ovarian follicles in the female (10 -15) and development and function of the testis in the male (16). Ovarian follicle formation and development is a dynamic process finely regulated by various intrinsic ...

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Section: Discussionsupporting

confidence: 79%

Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary

Kipp

Kilen

Woodruff

et al. 2007

Journal of Biological Chemistry

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“…A lower OSE cell height is indicative of an antiproliferative effect, as metaplastic changes of OSE are associated with columnar cell shapes and shorter cell morphology was reported to be associated with the presence of (putative) tumor suppressors (Smad 3, ERβ1) in the mouse (Symonds et al, 2003;Gulliver and Hurst, 2011). The reduction in OSE cell height was more pronounced in the DZ-exposed group than in the group exposed to EE.…”

mentioning

confidence: 84%

Prenatal Exposure to the Phytoestrogen Daidzein Resulted in Persistent Changes in Ovarian Surface Epithelial Cell Height, Folliculogenesis, and Estrus Phase Length in Adult Sprague-Dawley Rat Offspring

Talsness

Grote

Kuriyama

et al. 2015

Journal of Toxicology and Environmental Health, Part A

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Daidzein (DZ), an isoflavone with the potential to interfere with estrogen signaling, is found in soy products, which have gained popularity due to purported beneficial effects on the cardiovascular and skeletal systems and potential antineoplastic properties. However, the ingestion of phytoestrogens has been associated with impaired reproductive function in many species. The aim of this study was to determine the long-term effects on the ovaries of rat offspring exposed to DZ or ethinyl estradiol (EE) during prenatal development. Gravid rats were administered either vehicle or 5 or 60 mg DZ/kg body weight/d or 0.002 mg 17-α EE /kg body weight/d on gestational days 6-21. Ovarian-related endpoints were investigated during adulthood in female offspring. The mean cell height of the ovarian surface epithelium was significantly reduced in all treated groups. Alterations in folliculogenesis included increased follicular atresia, a reduction in secondary and tertiary follicle numbers, and cyst formation. An elevated prevalence of a slightly prolonged estrus phase was also observed. The morphological changes to the ovarian surface epithelium are consistent with an antiproliferative effect, while ovarian folliculogenesis was adversely affected. The effects of the high dose DZ were similar to those observed with 17-α EE.

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“…Sections were cut at 5 m and subjected to staining for PCNA using a commercially available monoclonal antibody (1:100 dilution; Oncogene Research Products, Boston, MA) as described previously (22,24). The biotinylated streptavidin Histomouse-SP system (Zymed Laboratories, Inc., San Francisco, CA) with background blocking was used with 3-amino-9-ethyl carbazole chromogenic visualization and Mayer's hematoxylin counterstaining.…”

Section: Measurement Of Proliferation In the Ovarymentioning

confidence: 99%

“…Downstream Smad signaling proteins might be the essential determinants of the different actions of TGF␤ superfamily members, but little is known about their function in the mammalian ovary. Smad3 is a receptor regulated Smad, and it is highly expressed in the ovarian surface epithelium, granulosa cells, and oocytes of several animal models (21)(22)(23)(24). Smad3 and its closely related homolog Smad2, mediate intracellular signaling pathways from TGF␤ and activin, each of which has been implicated as an important factor in ovarian development and function (3,4).…”

mentioning

confidence: 99%

Ovarian Follicle Development Requires Smad3

Tomic

Miller

Kenny³

et al. 2004

Molecular Endocrinology

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114

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Smad3 is an important mediator of the TGF beta signaling pathway. Interestingly, Smad3-deficient (Smad3-/-) mice have reduced fertility compared with wild-type (WT) mice. To better understand the molecular mechanisms underlying the reduced fertility in Smad3-/- animals, this work tested the hypothesis that Smad3 deficiency interferes with three critical aspects of folliculogenesis: growth, atresia, and differentiation. Growth was assessed by comparing the size of follicles, expression of proliferating cell nuclear antigen, and expression of cell cycle genes in Smad3-/- and WT mice. Atresia was assessed by comparing the incidence of atresia and expression of bcl-2 genes involved in cell death and cell survival in Smad3-/- and WT mice. Differentiation was assessed by comparing the expression of FSH receptor (FSHR), estrogen receptor (ER) alpha, ER beta, and inhibin alpha-, beta(A)-, and beta(B)-subunits in Smad3-/- and WT mice. Because growth, atresia, and differentiation are regulated by hormones, estradiol, FSH, and LH levels were compared in Smad3-/- and WT mice. Moreover, because alterations in folliculogenesis can affect the ability of mice to ovulate, the number of corpora lutea and ovulated eggs in response to gonadotropin treatments were compared in Smad3-/- and WT animals. The results indicate that Smad3 deficiency slows follicle growth, which is characterized by small follicle diameters, low levels of proliferating cell nuclear antigen, and low expression of cell cycle genes (cyclin-dependent kinase 4 and cyclin D2). Smad3 deficiency also causes atretic follicles, degenerated oocytes, and low expression of bcl-2. Furthermore, Smad3 deficiency affects follicular differentiation as evidenced by decreased expression of ER beta, increased expression of ER alpha, and decreased expression of inhibin alpha-subunits. Smad3 deficiency causes low estradiol and high FSH levels. Finally, Smad3-/- ovaries have no corpora lutea, and they do not ovulate after ovulatory induction with exogenous gonadotropins. Collectively, these data provide the first evidence that reduced fertility in Smad3-/- mice is due to impaired folliculogenesis, associated with altered expression of genes that control cell cycle progression, cell survival, and cell differentiation. The findings that Smad3-/- follicles have impaired growth, increased atresia, and altered differentiation in the presence of high FSH levels, normal expression of FSHR, and lower expression of cyclin D2, suggest a possible interaction between Smad3 and FSH signaling downstream of FSHR in the mouse ovary.

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Smad 3 regulates proliferation of the mouse ovarian surface epithelium

Cited by 17 publications

References 24 publications

Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary

Activin Regulates Estrogen Receptor Gene Expression in the Mouse Ovary

Prenatal Exposure to the Phytoestrogen Daidzein Resulted in Persistent Changes in Ovarian Surface Epithelial Cell Height, Folliculogenesis, and Estrus Phase Length in Adult Sprague-Dawley Rat Offspring

Ovarian Follicle Development Requires Smad3

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