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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.

Authors

Claire Glister

Leanne Satchell

Ross A.D. Bathgate

John D. Wade

Yanzhenzhi Dai

Richard Ivell richard.ivell@nottingham.ac.uk

Raymond J. Rodgers

Philip G. Knight



Abstract

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.

Citation

Glister, C., Satchell, L., Bathgate, R. A., Wade, J. D., Dai, Y., Ivell, R., …Knight, P. 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), https://doi.org/10.1073/pnas.1222216110

Journal Article Type Article
Acceptance Date Feb 26, 2013
Online Publication Date Mar 25, 2013
Publication Date Apr 9, 2013
Deposit Date Mar 22, 2017
Publicly Available Date Mar 22, 2017
Journal Proceedings of the National Academy of Sciences
Print ISSN 0027-8424
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 110
Issue 15
Article Number E1426-E1435
DOI https://doi.org/10.1073/pnas.1222216110
Keywords Growth factor ; ovary ; reproduction
Public URL http://eprints.nottingham.ac.uk/id/eprint/41443
Publisher URL http://www.pnas.org/content/110/15/E1426
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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