Investigations of TGF-β Signaling in Preantral Follicles of Female Mice Reveal Differential Roles for Bone Morphogenetic Protein 15

Fenwick, Mark A.; Mora, Jocelyn; Mansour, Yosef T.; Baithun, Christina; Hardy, Kate

doi:10.1210/en.2012-2251

Cited by 42 publications

(48 citation statements)

References 74 publications

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“…6). Similar stimulation of both proliferation and apoptosis was observed previously in follicles cultured in the presence of BMP15 and GDF9 together (26), suggesting an increase in cell turnover may be induced as a self-regulatory mechanism to prevent excessive follicle growth. The observed increase in apoptosis in the presence of FSH may be due to inhibition of antiapoptotic factors or stimulation of proapoptotic factors by FSH.…”

Section: Discussionsupporting

confidence: 81%

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Onset and Heterogeneity of Responsiveness to FSH in Mouse Preantral Follicles in Culture

et al. 2016

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The obligatory role of follicle-stimulating hormone (FSH) in normal development and function of ovarian antral follicles is well recognized, but its function in preantral growth is less clear. The specific objective of this study was to investigate the response, in culture, to FSH of mouse preantral follicles of increasing size, focusing particularly on growth rate and gene expression. Preantral follicles were mechanically isolated from ovaries of C57BL/6 mice, 12 to 16 days postpartum, and single follicles cultured for up to 96 hours in medium alone (n = 511) or with recombinant human FSH 10 ng/mL (n = 546). Data were grouped according to initial follicle diameter in 6 strata ranging from <100 to >140 μm. Follicles of all sizes grew in the absence of FSH (P < 0.01, paired t test). All follicles grew at a faster rate (P < 0.0001) in the presence of 10 ng/mL FSH but larger follicles showed the greatest change in response to FSH. Even the smallest follicles expressed FSH receptor messenger RNA (mRNA). FSH-induced growth was inhibited by KT5720, an inhibitor of protein kinase A (PKA), implicating the PKA pathway in FSH-induced follicle growth. In response to FSH in vitro, FSH receptor mRNA (measured by quantitative polymerase chain reaction) was reduced (P < 0.01), as was Amh (P < 0.01), whereas expression of StAR (P < 0.0001) and the steroidogenic enzymes Cyp11a1 (P < 0.01) and Cyp19 (P < 0.0001) was increased. These results show heterogeneous responses to FSH according to initial follicle size, smaller follicles being less FSH dependent than larger preantral follicles. These findings strongly suggest that FSH has a physiological role in preantral follicle growth and function.

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Section: Discussionsupporting

confidence: 81%

“…At the end of culture, follicles were fixed in 10% neutral buffered formalin (Sigma) and processed for immunofluorescence analysis of GC apoptosis [terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), cleaved caspase-3] and proliferation (Ki67), as previously described (26). Antibodies are listed in Table 1.…”

Section: Methodsmentioning

confidence: 99%

Onset and Heterogeneity of Responsiveness to FSH in Mouse Preantral Follicles in Culture

et al. 2016

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“…BMP15 encodes a protein associated to oocyte maturation, and follicular development (Fenwick et al, 2013; Persani et al, 2014; Sutton-McDowall et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Transcriptional Network Architecture of Breast Cancer Molecular Subtypes

et al. 2016

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Breast cancer heterogeneity is evident at the clinical, histological and molecular level. High throughput technologies allowed the identification of intrinsic subtypes that capture transcriptional differences among tumors. A remaining question is whether said differences are associated to a particular transcriptional program which involves different connections between the same molecules. In other words, whether particular transcriptional network architectures can be linked to specific phenotypes. In this work we infer, construct and analyze transcriptional networks from whole-genome gene expression microarrays, by using an information theory approach. We use 493 samples of primary breast cancer tissue classified in four molecular subtypes: Luminal A, Luminal B, Basal and HER2-enriched. For comparison, a network for non-tumoral mammary tissue (61 samples) is also inferred and analyzed. Transcriptional networks present particular architectures in each breast cancer subtype as well as in the non-tumor breast tissue. We find substantial differences between the non-tumor network and those networks inferred from cancer samples, in both structure and gene composition. More importantly, we find specific network architectural features associated to each breast cancer subtype. Based on breast cancer networks' centrality, we identify genes previously associated to the disease, either, generally (i.e., CNR2) or to a particular subtype (such as LCK). Similarly, we identify LUZP4, a gene barely explored in breast cancer, playing a role in transcriptional networks with subtype-specific relevance. With this approach we observe architectural differences between cancer and non-cancer at network level, as well as differences between cancer subtype networks which might be associated with breast cancer heterogeneity. The centrality measures of these networks allow us to identify genes with potential biomedical implications to breast cancer.

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“…The BMP15 and GDF9 signals activate downstream Smad transcription factors via specific complexes formed by binding to type I and type II receptors. The expression of BMP15 type I receptor ALK6 and GDF9 type I receptor ALK5 can be detected in rodent granulosa cells and oocytes; the common type II receptor BMPR2 can also be detected [14], and ALK4 may be the receptor for GDF9 [15]. BMPR2 is essential to the transportation of oocyte signals that act paracrine to cumulus cells and is the only type II receptor for BMP15 and GDF9 [16].…”

Section: Introductionmentioning

confidence: 99%

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

Liu¹,

Yuan²,

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), which are secreted by oocytes, are important regulators of follicular growth and development and ovarian function. These two factors can regulate the proliferation and apoptosis of cumulus cells via modulation of the Smad signaling pathway. Studies have shown that BMP15 and GDF9 can affect the level of miR-375, whereas the target gene of miR-375 is BMPR2, the type II receptor of BMP15 and GDF9. However, whether or how the BMP15/ GDF9-miR-375-BMPR2 pathway affects the proliferation and apoptosis of bovine cumulus cells through regulation of the Smad signaling pathway remains unclear. Methods: In this study, cumulus cells were first obtained from cumulus-oocyte complexes (COCs). Appropriate concentrations of BMP15 and GDF9 were added during the in vitro culture process. Cell Counting Kit-8 (CCK-8) analyses and flow cytometry were used to determine the effects of BMP15/GDF9 on bovine cumulus cells proliferation and apoptosis. Subsequently, miR-375 mimics, miR-375 inhibitor and BMPR2 siRNA were synthesized and used for transfection experiments. Western Blot analysis was used to detect changes before and after transfection in the expression levels of the BMP15/GDF9 type I receptors ALK4, ALK5 and ALK6; the phosphorylation levels of Smad2/3 and Smad1/5/8, which are key signaling pathway proteins downstream of BMP15/GDF9; the expression levels of PTX3, HAS2 and PTGS2, which are key genes involved in cumulus cells proliferation; and Bcl2/Bax, which are genes involved in apoptosis. Results: The addition of 100 ng/mL BMP15 or 200 ng/mL GDF9 or the combined addition of 50 ng/mL BMP15 and 100 ng/mL GDF9 effectively inhibited bovine cumulus cell apoptosis and promoted cell proliferation. BMP15/GDF9 negatively regulated miR-375 expression and positively regulated BMPR2 expression. High levels of miR-375 and inhibition of BMPR2 resulted in increased expression of ALK4 and decreased expression of PTX3, HAS2 and PTGS2, whereas miR-375 inhibition resulted in the opposite results. BMP15 and GDF9 significantly activated the levels of p-Smad2/3 and p-Smad1/5/8, whereas miR-375 inhibited the levels of p-Smad2/3 and p-Smad1/5/8 by negatively regulating BMPR2 and also led to apoptosis. Conclusion: BMP15 and GDF9 have synergistic effects and can act through miR-375 to affect the expression levels of type I receptor ALK4 and type II receptor BMPR2 and the activation of Smad signaling pathway, which subsequently affected the proliferation, spread and apoptosis of cumulus cells.

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Investigations of TGF-β Signaling in Preantral Follicles of Female Mice Reveal Differential Roles for Bone Morphogenetic Protein 15

Cited by 42 publications

References 74 publications

Onset and Heterogeneity of Responsiveness to FSH in Mouse Preantral Follicles in Culture

Onset and Heterogeneity of Responsiveness to FSH in Mouse Preantral Follicles in Culture

Transcriptional Network Architecture of Breast Cancer Molecular Subtypes

Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

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