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?-catenin regulates GnRH-induced FSH? gene expression.

ABSTRACT: The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of ?-catenin in LH? induction by GnRH has been discovered. We examined the role of ?-catenin in FSH? gene expression in L?T2 gonadotrope cells. GnRH caused a sustained increase in nuclear ?-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JNK) inhibition. Small interfering RNA-mediated knockdown of ?-catenin mRNA demonstrated that induction of FSH? mRNA by GnRH depended on ?-catenin and that regulation of FSH? by ?-catenin occurred independently of the JNK-c-jun pathway. ?-Catenin depletion had no impact on FSH? mRNA stability. In L?T2 cells transfected with FSH? promoter luciferase fusion constructs, GnRH responsiveness was conferred by the proximal promoter (-944/-1) and was markedly decreased by ?-catenin knockdown. However, none of the T-cell factor/lymphoid enhancer factor binding sites in that region were required for promoter activation by GnRH. Chromatin immunoprecipitation further corroborated the absence of direct interaction between ?-catenin and the 1.8-kb FSH? promoter. To elucidate the mechanism for the ?-catenin effect, we analyzed approximately 1 billion reads of next-generation RNA sequencing ?-catenin knockdown assays and selected the nuclear cofactor breast cancer metastasis-suppressor 1-like (Brms1L) as one candidate for further study. Subsequent experiments confirmed that Brms1L mRNA expression was decreased by ?-catenin knockdown as well as by JNK inhibition. Furthermore, knockdown of Brms1L significantly attenuated GnRH-induced FSH? expression. Thus, our findings indicate that the expression of Brms1L depends on ?-catenin activity and contributes to FSH? induction by GnRH.

SUBMITTER: Wang Q

PROVIDER: S-EPMC3683805 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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β-catenin regulates GnRH-induced FSHβ gene expression.

Wang Qian Q Chikina Maria M Zaslavsky Elena E Pincas Hanna H Sealfon Stuart C SC

Molecular endocrinology (Baltimore, Md.) 20121204 2

The regulation of gonadotropin synthesis by GnRH plays an essential role in the neuroendocrine control of reproduction. The known signaling mechanisms involved in gonadotropin synthesis have been expanding. For example, involvement of β-catenin in LHβ induction by GnRH has been discovered. We examined the role of β-catenin in FSHβ gene expression in LβT2 gonadotrope cells. GnRH caused a sustained increase in nuclear β-catenin levels, which was significantly reduced by c-Jun N-terminal kinase (JN ...[more]

PMID: 23211523

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Project description:Abstract Polycystic ovary syndrome (PCOS) is the most common cause of female infertility and is associated with an increased risk of type 2 diabetes and cardiovascular disease. Understanding the etiology of PCOS is crucial to relieve this tremendous health burden. Twin studies estimate that 70% of PCOS etiology can be explained by genetic factors, motivating studies to identify these factors. Recent genome wide association studies identified a PCOS risk locus that encompasses the gene encoding the follicle-stimulating hormone beta (FSHβ) subunit. The most significant single nucleotide polymorphism (SNP) within this locus, rs11031006 (rs06), resides within a region of DNA (~450 base pairs) that is highly conserved among mammals. As FSH supplementation can restore ovulation in some PCOS patients, deficient FSH signaling may be a causative factor of anovulation and potentially other facets of PCOS. FSH transcription and release is stimulated by gonadotropin-releasing hormone (GnRH) produced in the hypothalamus, as well as activin produced by the gonads and pituitary. We previously hypothesized that the conserved region containing rs06 acts as an enhancer of FSHβ transcription, and we determined through luciferase reporter assays that this highly conserved region enhances transcription ~2 fold compared to the minimal FSHβ promoter alone for human and 2.5 fold for mouse. The rs06 SNP minor allele further increased both mouse and human FSHβ luciferase expression. In the present study, we sought to identify interactions between the enhancer and the hormones, GnRH and activin. With DNA constructs from both human and mouse, we identified synergistic interactions between the enhancer and GnRH- or activin-induction of FSHβ. These interactions were maintained after mutation of the rs06 site to the minor allele, suggesting that this SNP alters basal and not hormone-induced FSHβ transcription. We are currently investigating the effect of the enhancer and rs06 on activin/GnRH synergy. Overall, our findings provide evidence that the enhancer functions as a novel mediator of activin and GnRH regulation of FSHβ transcription in both human and mouse.

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?-catenin regulates GnRH-induced FSH? gene expression.

Publications

β-catenin regulates GnRH-induced FSHβ gene expression.

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