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Attenuation of Bone Morphogenetic Proteins (BMPs) Signaling Induces Granulosa Cell Sensitivity to Gonadotropins in Female Mouse .


Affiliations
1 Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick 08901, NJ, USA ., India
2 School of Science and Technology, University of New England, Armidale 2351, NSW, Australia, India
3 School of Science and Technology, University of New England, Armidale 2351, NSW, Australia ., India
4 Curtin Medical School, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Bentley 6012, WA, Australia ., India
     

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Several lines of evidence support the notion that Bone Morphogenetic Proteins (BMPs) and gonadotropic hormones are major regulators of ovarian follicle development by inducing gonadotropin-mediated steroid hormone production and regulating ovarian follicle cell proliferation. Research from our laboratory and elsewhere have demonstrated that BMPs play important roles during the early stages of folliculogenesis. Despite the extensive research to reveal the mechanism of interaction between BMPs and gonadotropic hormones in the process of folliculogenesis, the exact mechanism of such an interaction is not adequately understood. Previously, we developed a unique mouse model characterized by a short-term attenuation of the BMP signaling system using passive immunization against bone morphogenetic protein 4 (BMP-4) and bone morphogenetic protein receptor 1B (BMPR1B). This model unequivocally demonstrated that the attenuation of BMP action was an effective method of enhancing fertility reserve and promoting follicle and ovulation rates in female mice. In addition, this study pointed to the possibility of bi-directional mutual regulation between BMPs, Follicle-Stimulating Hormone (FSH), and Luteinizing Hormone (LH). To gain further insight into this mechanism we used this mouse model to examine the protein expression and mRNA level of BMPR1B, Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) in multiple stages of follicle development in female mice. Immunofluorescent analysis of female mice treated with anti-BMPR1B antibodies showed a significant upregulation of BMPR1B, FSHR, and LHCGR in the ovarian granulosa cells during the main stages of follicle development, whereas treatment with anti-BMP4 antibodies showed no effect. In addition, attenuation of BMPR1B resulted in upregulation of the FSHR (exclusively expressed in the granulosa cell) and LHCGR mRNA levels in the ovary. The present study implies that BMPs engage indirectly in regulating the later stages of folliculogenesis, in addition to their direct role in the regulation of the early stages of follicle development, by enhancing granulosa cell sensitivity to gonadotropins through upregulating the receptor expression. We propose that our mouse model is siutable to elucidate the mechanism of interaction between BMPs and gonadotropins in folliculogenesis.

Keywords

BMP-4, BMPR1B, FSHR, Gene Expression, Immunization, Immunofluorescence, LHCGR, Protein Expression,
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  • Attenuation of Bone Morphogenetic Proteins (BMPs) Signaling Induces Granulosa Cell Sensitivity to Gonadotropins in Female Mouse .

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Authors

Sarmed Al-Samerria
Laboratory of Human Growth and Reproductive Development, Department of Pediatrics, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick 08901, NJ, USA ., India
Suresh K. A. Palanisamy
School of Science and Technology, University of New England, Armidale 2351, NSW, Australia, India
Ibtisam Al-Ali
School of Science and Technology, University of New England, Armidale 2351, NSW, Australia ., India
Cyril D. Mamotte
Curtin Medical School, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Bentley 6012, WA, Australia ., India
James R. McFarlane
School of Science and Technology, University of New England, Armidale 2351, NSW, Australia ., India
Ghanim Almahbobi
Curtin Medical School, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Bentley 6012, WA, Australia ., India

Abstract


Several lines of evidence support the notion that Bone Morphogenetic Proteins (BMPs) and gonadotropic hormones are major regulators of ovarian follicle development by inducing gonadotropin-mediated steroid hormone production and regulating ovarian follicle cell proliferation. Research from our laboratory and elsewhere have demonstrated that BMPs play important roles during the early stages of folliculogenesis. Despite the extensive research to reveal the mechanism of interaction between BMPs and gonadotropic hormones in the process of folliculogenesis, the exact mechanism of such an interaction is not adequately understood. Previously, we developed a unique mouse model characterized by a short-term attenuation of the BMP signaling system using passive immunization against bone morphogenetic protein 4 (BMP-4) and bone morphogenetic protein receptor 1B (BMPR1B). This model unequivocally demonstrated that the attenuation of BMP action was an effective method of enhancing fertility reserve and promoting follicle and ovulation rates in female mice. In addition, this study pointed to the possibility of bi-directional mutual regulation between BMPs, Follicle-Stimulating Hormone (FSH), and Luteinizing Hormone (LH). To gain further insight into this mechanism we used this mouse model to examine the protein expression and mRNA level of BMPR1B, Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone/Choriogonadotropin Receptor (LHCGR) in multiple stages of follicle development in female mice. Immunofluorescent analysis of female mice treated with anti-BMPR1B antibodies showed a significant upregulation of BMPR1B, FSHR, and LHCGR in the ovarian granulosa cells during the main stages of follicle development, whereas treatment with anti-BMP4 antibodies showed no effect. In addition, attenuation of BMPR1B resulted in upregulation of the FSHR (exclusively expressed in the granulosa cell) and LHCGR mRNA levels in the ovary. The present study implies that BMPs engage indirectly in regulating the later stages of folliculogenesis, in addition to their direct role in the regulation of the early stages of follicle development, by enhancing granulosa cell sensitivity to gonadotropins through upregulating the receptor expression. We propose that our mouse model is siutable to elucidate the mechanism of interaction between BMPs and gonadotropins in folliculogenesis.

Keywords


BMP-4, BMPR1B, FSHR, Gene Expression, Immunization, Immunofluorescence, LHCGR, Protein Expression,

References