Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production
Bone morphogenetic proteins (BMPs) are firmly implicated as intraovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated ex...
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National Academy of Sciences
2013
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| Online Access: | https://eprints.nottingham.ac.uk/41443/ |
| _version_ | 1848796274652872704 |
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| author | Glister, Claire Satchell, Leanne Bathgate, Ross A.D. Wade, John D. Dai, Yanzhenzhi Ivell, Richard Anand-Ivell, Ravinder Rodgers, Raymond J. Knight, Philip G. |
| author_facet | Glister, Claire Satchell, Leanne Bathgate, Ross A.D. Wade, John D. Dai, Yanzhenzhi Ivell, Richard Anand-Ivell, Ravinder Rodgers, Raymond J. Knight, Philip G. |
| author_sort | Glister, Claire |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Bone morphogenetic proteins (BMPs) are firmly implicated as intraovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3)was themost heavily down-regulated gene (−43-fold)with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also downregulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ∼twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling. |
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| format | Article |
| id | nottingham-41443 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:45:23Z |
| publishDate | 2013 |
| publisher | National Academy of Sciences |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-414432020-05-04T16:36:31Z https://eprints.nottingham.ac.uk/41443/ Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production Glister, Claire Satchell, Leanne Bathgate, Ross A.D. Wade, John D. Dai, Yanzhenzhi Ivell, Richard Anand-Ivell, Ravinder Rodgers, Raymond J. Knight, Philip G. Bone morphogenetic proteins (BMPs) are firmly implicated as intraovarian regulators of follicle development and steroidogenesis. Here we report a microarray analysis showing that treatment of cultured bovine theca cells (TC) with BMP6 significantly (>twofold; P < 0.01) up- or down-regulated expression of 445 genes. Insulin-like peptide 3 (INSL3)was themost heavily down-regulated gene (−43-fold)with cytochrome P450, subfamily XVII (CYP17A1) and other key steroidogenic transcripts including steroidogenic acute regulatory protein (STAR), cytochrome P450 family 11, subfamily A1 (CYP11A1) and 3 beta-hydroxysteroid dehydrogenase type 1 (HSD3B1) also downregulated. BMP6 also reduced expression of nuclear receptor subfamily 5A1 (NR5A1) known to target the promoter regions of the aforementioned genes. Real-time PCR confirmed these findings and also revealed a marked reduction in expression of INSL3 receptor, relaxin/insulin-like family peptide receptor 2 (RXFP2). Secretion of INSL3 protein and androstenedione were also suppressed suggesting a functional link between BMP and INSL3 pathways in controlling androgen synthesis. RNAi-mediated knockdown of INSL3 reduced INSL3 mRNA (75%) and protein (94%) level and elicited a 77% reduction in CYP17A1 mRNA and 83% reduction in androstenedione secretion. Knockdown of RXFP2 also reduced CYP17A1 expression (81%) and androstenedione secretion (88%). Conversely, treatment with exogenous (human) INSL3 increased androstenedione secretion ∼twofold. The CYP17A1 inhibitor abiraterone abolished androgen secretion and reduced expression of both INSL3 and RXFP2. Collectively, these findings indicate a positive autoregulatory role for INSL3 signaling in maintaining thecal androgen production, and visa versa. Moreover, BMP6-induced suppression of thecal androgen synthesis may be mediated, at least in part, by reduced INSL3-RXFP2 signaling. National Academy of Sciences 2013-04-09 Article PeerReviewed Glister, Claire, Satchell, Leanne, Bathgate, Ross A.D., Wade, John D., Dai, Yanzhenzhi, Ivell, Richard, Anand-Ivell, Ravinder, Rodgers, Raymond J. and Knight, Philip G. (2013) Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production. Proceedings of the National Academy of Sciences, 110 (15). E1426-E1435. ISSN 1091-6490 Growth factor ; ovary ; reproduction http://www.pnas.org/content/110/15/E1426 doi:10.1073/pnas.1222216110 doi:10.1073/pnas.1222216110 |
| spellingShingle | Growth factor ; ovary ; reproduction Glister, Claire Satchell, Leanne Bathgate, Ross A.D. Wade, John D. Dai, Yanzhenzhi Ivell, Richard Anand-Ivell, Ravinder Rodgers, Raymond J. Knight, Philip G. Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| title | Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| title_full | Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| title_fullStr | Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| title_full_unstemmed | Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| title_short | Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| title_sort | functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production |
| topic | Growth factor ; ovary ; reproduction |
| url | https://eprints.nottingham.ac.uk/41443/ https://eprints.nottingham.ac.uk/41443/ https://eprints.nottingham.ac.uk/41443/ |