Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production

Glister, Claire and Satchell, Leanne and Bathgate, Ross A.D. and Wade, John D. and Dai, Yanzhenzhi and Ivell, Richard and Anand-Ivell, Ravinder and 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

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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.

Item Type: Article
Keywords: Growth factor ; ovary ; reproduction
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Biosciences > Division of Animal Sciences
Identification Number: 10.1073/pnas.1222216110
Depositing User: Anand-Ivell, Dr Ravinder
Date Deposited: 22 Mar 2017 11:45
Last Modified: 23 Mar 2017 08:42
URI: http://eprints.nottingham.ac.uk/id/eprint/41443

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