Dataset Information

Augmentation of Nr4a3 and Suppression of Fshb Expression in the Pituitary Gland of Female Annexin A5 Null Mouse.

ABSTRACT: GnRH enhances the expression of annexin A5 (ANXA5) in pituitary gonadotropes, and ANXA5 enhances gonadotropin secretion. However, the impact of ANXA5 regulation on the expression of pituitary hormone genes remains unclear. Here, using quantitative PCR, we demonstrated that ANXA5 deficiency in female mice reduced the expression of Fshb and Gh in their pituitary glands. Transcriptome analysis confirmed a specific increase in Nr4a3 mRNA expression in addition to lower levels of Fshb expression in ANXA5-deficient female pituitary glands. This gene was then found to be a GnRH-inducible immediate early gene, and its increased expression caused protein to accumulate in the nucleus after administration of a GnRH agonist in L?T2 cells, which are an in vitro pituitary gonadotrope model. The increase in ANXA5 protein levels in L?T2 cells clearly suppressed Nr4a3 expression. siRNA-mediated inhibition of Nr4a3 expression increased Fshb expression. The results revealed that GnRH stimulates Nr4a3 and Anxa5 sequentially. NR4A3 suppression of Fshb may be necessary for later massive secretion of FSH by GnRH in gonadotropes, and Nr4a3 would be negatively regulated by ANXA5 to increase FSH secretion.

SUBMITTER: Terashima R

PROVIDER: S-EPMC7448937 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Augmentation of Nr4a3 and Suppression of Fshb Expression in the Pituitary Gland of Female Annexin A5 Null Mouse.

Terashima Ryota R Saigo Tomotaka T Laoharatchatathanin Titaree T Kurusu Shiro S Brachvogel Bent B Pöschl Ernst E Kawaminami Mitsumori M

Journal of the Endocrine Society 20200716 9

GnRH enhances the expression of annexin A5 (ANXA5) in pituitary gonadotropes, and ANXA5 enhances gonadotropin secretion. However, the impact of ANXA5 regulation on the expression of pituitary hormone genes remains unclear. Here, using quantitative PCR, we demonstrated that ANXA5 deficiency in female mice reduced the expression of Fshb and Gh in their pituitary glands. Transcriptome analysis confirmed a specific increase in Nr4a3 mRNA expression in addition to lower levels of ...[more]

PMID: 32864544

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Project description:Annexin A5 (ANXA5), which is known as a protein with anticoagulative function, may play a role in triglyceride biosynthesis. Triglycerides are involved in lipid and energy metabolism, which are important in the elucidation of obesity. To investigate the association between single-nucleotide polymorphisms (SNPs) of ANXA5 and obesity in a Korean population, 372 participants (213 overweight/obese individuals and 159 control subjects) were enrolled from the Kyung Hee University Medical Center and Keimyung University Dongsan Medical Center. The genotypes of five SNPs (rs12510548, rs4240260, rs3756281, rs13136094 and rs6534313) were evaluated in ANXA5 using the multiple logistic regression analysis with the codominant 1, codominant 2, dominant, recessive and log-additive models. The genotype and allele frequencies of the five investigated SNPs exhibited significant differences between the control and the overweight/obese groups: rs12510548 (P=0.004 in the codominant 2 model, P=0.0019 in the recessive model, P=0.027 in the log-additive model and P=0.026 in allele frequencies); rs4240260 (P=0.002 and Fisher's exact P=0.0006 in the codominant 2 model, P=0.0007 and Fisher's exact P=0.0007 in the recessive model, P=0.020 and Fisher's exact P=0.0019 in the log-additive model and P=0.020 in allele frequencies); rs3756281 (P=0.016 in the codominant 2 model and P=0.0094 in the recessive model); rs13136094 (P=0.0030 and Fisher's exact P=0.0011 in the codominant 2 model, P=0.0012 and Fisher's exact P=0.0013 in the recessive model, P=0.034 and Fisher's exact P=0.0035 in the log-additive model and P=0.024 in allele frequencies); and rs6534313 (P=0.0010 and Fisher's exact P=0.0003 in the codominant 2 model, P=0.0003 and Fisher's exact P=0.0003 in the recessive model, P=0.0075 and Fisher's exact P=0.0010 in the log-additive model and P=0.005 in allele frequencies). Two haplotypes were weakly associated with obesity (GGATG, P=0.037 and CAGCC, P=0.020). Results of the present study suggested that ANXA5 may be associated with the development of obesity in a Korean population.

Project description:Follicle-stimulating hormone (FSH) is a gonadotrope-derived heterodimeric glycoprotein. Both the common α- and hormone-specific β subunits contain Asn-linked N-glycan chains. Recently, macroheterogeneous FSH glycoforms consisting of β-subunits that differ in N-glycan number were identified in pituitaries of several species and subsequently the recombinant human FSH glycoforms biochemically characterized. Although chemical modification and in vitro site-directed mutagenesis studies defined the roles of N-glycans on gonadotropin subunits, in vivo functional analyses in a whole-animal setting are lacking. Here, we have generated transgenic mice with gonadotrope-specific expression of either an HFSHB(WT) transgene that encodes human FSHβ WT subunit or an HFSHB(dgc) transgene that encodes a human FSHβ(Asn7Δ 24Δ) double N-glycosylation site mutant subunit, and separately introduced these transgenes onto Fshb null background using a genetic rescue strategy. We demonstrate that the human FSHβ(Asn7Δ 24Δ) double N-glycosylation site mutant subunit, unlike human FSHβ WT subunit, inefficiently combines with the mouse α-subunit in pituitaries of Fshb null mice. FSH dimer containing this mutant FSHβ subunit is inefficiently secreted with very low levels detectable in serum. Fshb null male mice expressing HFSHB(dgc) transgene are fertile and exhibit testis tubule size and sperm number similar to those of Fshb null mice. Fshb null female mice expressing the mutant, but not WT human FSHβ subunit-containing FSH dimer are infertile, demonstrate no evidence of estrus cycles, and many of the FSH-responsive genes remain suppressed in their ovaries. Thus, HFSHB(dgc) unlike HFSHB(WT) transgene does not rescue Fshb null mice. Our genetic approach provides direct in vivo evidence that N-linked glycans on FSHβ subunit are essential for its efficient assembly with the α-subunit to form FSH heterodimer in pituitary. Our studies also reveal that N-glycans on FSHβ subunit are essential for FSH secretion and FSH in vivo bioactivity to regulate gonadal growth and physiology.

Dataset Information

Augmentation of Nr4a3 and Suppression of Fshb Expression in the Pituitary Gland of Female Annexin A5 Null Mouse.

Publications

Augmentation of <i>Nr4a3</i> and Suppression of <i>Fshb</i> Expression in the Pituitary Gland of Female Annexin A5 Null Mouse.

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