Reporter transgenic mouse models highlight the dual endocrine and neural facet of GnRH receptor function

Schang, Anne-Laure; Counis, Raymond; Magre, Solange; Bleux, Christian; Granger, Anne; Ngô-Muller, Valérie; Chenut, Marie-Claude; Cohen‐Tannoudji, Joëlle; Laverrière, Jean-Noël

doi:10.1111/j.1749-6632.2010.05886.x

Cited by 8 publications

(12 citation statements)

References 43 publications

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“…Transgene expression was directed to pituitary gonadotrope cells in both mouse lines, thus supporting our in vitro data in gonadotrope cell lines, indicating that the 1.1 kb promoter sequence was necessary and sufficient for pituitary-specific expression (Granger et al 2004). Recently, we have reported transgene expression in the testis (Schang et al 2011a).…”

Section: Introductionsupporting

confidence: 84%

“…These transgenic mice were initially generated to improve in vitro analyses of the mechanisms involved in promoter activity and, most importantly, to explore, in vivo, the developmental pattern of rat Gnrhr promoter activity in the pituitary (Pincas et al 2001, Granger et al 2004, Schang et al 2013a. These transgenic mice also appeared to be powerful tools to identify novel tissues in which the Gnrhr promoter is active (Schang et al 2011a(Schang et al ,b, 2013b. Two transgenic mouse lines expressing ALPP under the control of the 3.3 or 1.1 kb rat Gnrhr promoter (referred to as 3.3-Gnrhr and 1.1-Gnrhr respectively) were generated.…”

Section: Introductionmentioning

confidence: 99%

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Rat Gnrhr promoter directs species-specific gene expression in the pituitary and testes of transgenic mice

Schang

Magre

Laverrière

et al. 2013

Journal of Molecular Endocrinology

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The GnRH receptor (GnRHR) is expressed in several non-pituitary tissues, notably in gonads. However, mechanisms underlying the gonad-specific expression of Gnrhr are not well understood. Here, Gnrhr expression was analysed in the developing testes and pituitaries of rats and transgenic mice bearing the human placental alkaline phosphatase reporter gene (ALPP) under the control of the rat Gnrhr promoter. We showed that the 3.3 kb, but not the pituitary-specific 1.1 kb promoter, directs ALPP expression exclusively to testis Leydig cells from embryonic day 12 onwards. Real-time PCR analysis revealed that promoter activity displayed the same biphasic profile as marker genes in Leydig cells, i.e. abrupt declines after birth followed by progressive rises after a latency phase, in coherence with the differentiation and evolution of foetal and adult Leydig cell lineages. Interestingly, the developmental profile of transgene expression showed high similarity with the endogenous Gnrhr profile in the rat testis, while mouse Gnrhr was only poorly expressed in the mouse testis. In the pituitary, both transgene and Gnrhr were co-expressed at measurable levels with similar ontogenetic profiles, which were markedly distinct from those in the testis. Castration that induced pituitary Gnrhr up-regulation in rats did not affect the mouse Gnrhr. However, it duly up-regulated the transgene. In addition, in LbT2 cells, the rat, but not mouse, Gnrhr promoter was sensitive to GnRH agonist stimulation. Collectively, our data highlight inter-species variations in the expression and regulation of Gnrhr in two different organs and reveal that the rat promoter sequence contains relevant genetic information that dictates rat-specific gene expression in the mouse context.

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Section: Introductionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Rat Gnrhr promoter directs species-specific gene expression in the pituitary and testes of transgenic mice

Schang

Magre

Laverrière

et al. 2013

Journal of Molecular Endocrinology

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“…The expression of brain GnRHR occurs after birth and is restricted to postmitotic neurons; 25 this excludes their involvement in neuronal embryonic development and suggests a possible role in postnatal development or in brain plasticity. Actually, activation of GnRHR alters the electrical properties of hippocampal neurons through a protein kinase C-dependent action 10 and exerts a significant control of synaptic plasticity.…”

Section: Discussionmentioning

confidence: 96%

“…27 GnRH was found to regulate the expression of pre-and post-synaptic markers spinophilin, synaptophisin and Egr1 in neurons obtained from hippocampus. 25,28 Hippocampal GnRHR has been implicated in the regulation of aromatase activity, 28 suggesting that the observed neurotrophic effect of GnRH could be mediated by a possible intervention on local synthesis of estrogen, known to affect synaptogenesis and expression of both spinophilin and synaptophysin. 29 This observation also suggests that estrus cycle -dependent synaptogenesis, occurring in the rat female hippocampus, may be regulated by the cyclic release of hypothalamic GnRH.…”

Section: Discussionmentioning

confidence: 99%

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

Maggi¹

2016

MOJAP

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Abbreviations: cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-triphosphate; HPG, hypothalamic-pituitary-gonadal; APP, amyloid precursor protein; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal-regulated kinase; PI3K, phosphatidylinositol-3-kinase; EGR1, early growth response 1; PP, phosphotyrosine phosphatase; NF-Kb, nuclear factor kappa-light-chain-enhancer of activated b cells; DHCR24, 3-betahydroxysterol delta-24-reductase; St AR, steroidogenic acute regulatory protein; IKK-β, inhibitor of nuclear factor kappa-b kinase subunit beta; Aβ, amyloid beta peptide IntroductionGonadotropin releasing hormone (GnRH) is 35year-old neuropeptide recognized as the central regulator of reproductive functions.1 It was actually one of the earliest hypothalamic-releasing hormones sequenced and characterized and led its discoverer Andrew Schally to be awarded by the Nobel prize in 1977. 2 The peptide is a sequence of ten aminoacids ( Figure 1A) with a cyclized proline at the N-terminal and a glycine-amide residue at C-terminal, which confer some resistance to terminal peptidases.In mammals, GnRH is mainly produced by a limited number of hypothalamic neurons, which do not form a defined nucleus but show a dispersed organization in the mediobasal hypothalamus. Making axonal contacts with the hypothalamo-hypophyseal portal vessels, GnRH neurons release the decapeptide in the bloodstream directed to the adenohypophysis in a pulsatile manner. 3 At the pituitary level, the decapeptide interact with specific G protein-coupled receptors (GnRHR) present on gonadotrope cells inducing the release of the two gonadotropins (LH, luteinizing hormone and FSH, follicle stimulating hormones) which in turn coordinate male and female gonadal functions promoting the folliculogenesis and the ovulation in female, the spermatogenesis in male, and the production of sex steroid hormones (estrogen, progesterone and testosterone) ( Figure 1B). 4,5 GnRHR may be coupled either to Gaq/11 or Gas subunits which activate different intracellular responses including cAMP and DAG/IP3 pathways, as well as the mitogen-activated protein kinase (MAPK) cascades. 6 The separate activation of Gaq/11 or Gas subunits, by changes in the frequency of decapeptide pulsatile release, is the basis for the differential control of gonadotropin release. 7The actions of GnRH on reproductive functions cover the whole lifespan and characterize the maturation, the pubertal activation and the adult functions of the hormonal hypothalamo-pituitary-gonadal axis. Because of its importance on reproductive functions, a series of synthetic analogues, with agonist or antagonist activities have been developed soon after GnRH identification (Table 1). 8,9The pharmacological approach with GnRH analogues has been so far limited to the induction of puberty or, more in general, for recovery of fertility through a pulsatile administration; on the contrary, a continuous administration of GnRH agonists or antagonist is used to block the gonadotropin r...

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“…The smaller response in the mixed cell preparation is likely due to the fact that PACAP mRNA produced by the folliculostellate cells is unchanged in response to GnRH. 7,50,51 Variations in the fold change across experiments may be the result of minor differences in the treatment protocols, such as differences in the vehicle or the length of incubation times that would have led to differences in paracrine factor involvement.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Gonadal Steroids and Gonadotropin-Releasing Hormone on Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and PACAP Receptor Expression in Cultured Rat Anterior Pituitary Cells

2014

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Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are expressed in the hypothalamus, the gonadotrope cells of the anterior pituitary gland, and the gonads, forming an autocrine-paracrine system in these tissues. Within the pituitary, PACAP functions either alone or synergistically with gonadotropin-releasing hormone (GnRH) to stimulate gonadotropin gene expression and secretion. Our goal was to define the hormonal regulation of pituitary PACAP and PACAP receptor (PAC1) gene expression by dihydrotestosterone (DHT), estradiol, and progesterone alone or in conjunction with GnRH. Treatment of adult male rat pituitary cell cultures with DHT or progesterone augmented GnRH-mediated increase in PACAP messenger RNA (mRNA) levels, but neither had an effect when present alone. Conversely, estradiol treatment blunted PACAP gene expression but did not alter GnRH effects on PACAP expression. Expression of PACAP receptor mRNA was decreased by GnRH treatment, minimally increased by DHT treatment, but not altered by the addition of estradiol or progesterone. DHT and GnRH together blunted PACAP receptor gene expression. Taken together, these results suggest that the activity of the intrapituitary PACAP-PAC1 system is regulated via the complex interaction of gonadal steroids and hypothalamic GnRH.

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Reporter transgenic mouse models highlight the dual endocrine and neural facet of GnRH receptor function

Cited by 8 publications

References 43 publications

Rat Gnrhr promoter directs species-specific gene expression in the pituitary and testes of transgenic mice

Rat Gnrhr promoter directs species-specific gene expression in the pituitary and testes of transgenic mice

Physiology of Gonadotropin-Releasing Hormone (Gnrh): Beyond the Control of Reproductive Functions

Interaction of Gonadal Steroids and Gonadotropin-Releasing Hormone on Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and PACAP Receptor Expression in Cultured Rat Anterior Pituitary Cells

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