The Insulin-Like Growth Factor System in the GT1-7 GnRH Neuronal Cell Line

Anderson, Richard A.; Zwain, Ismail; Arroyo, Amanda; Mellon, Pamela L.; Yen, S. S. C.

doi:10.1159/000054496

Cited by 38 publications

(28 citation statements)

References 33 publications

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“…In vitro stimulation of GnRH neurons with insulin increases GnRH expression and release (11,(14)(15)(16). IGF-1 stimulation also increases GnRH expression (17,18) and release (19) in vitro. We sought to determine whether direct action of insulin and IGF-1 on the GnRH neuron plays a role in regulation of puberty and reproduction in vivo.…”

Section: Introductionmentioning

confidence: 94%

Divergent roles of growth factors in the GnRH regulation of puberty in mice

et al. 2010

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Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states.

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Section: Introductionmentioning

confidence: 94%

Divergent roles of growth factors in the GnRH regulation of puberty in mice

et al. 2010

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“…Previous reports found that insulin did not increase GnRH release from the GT1-7 cell line, a GnRH secreting immortalized cell line, after two hours of insulin exposure in static culture (Olson et al, 1995;Anderson et al, 1999). At supraphysiologic concentrations, insulin has been shown to affect GnRH secretion in a model of conditionally immortalized and GnRH expressing rat hypothalamic neurons in perifusion experiments (Salvi et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin

DiVall

Radovick

Wolfe

2007

Molecular and Cellular Endocrinology

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SUMMARYInsulin increases gonadotropin-releasing hormone (GnRH) gene expression in in vitro models of GnRH neurons. Early growth response-1 (Egr-1) is a transcription factor that mediates the effect of insulin on target genes. In the GN11 cell line-an immortalized GnRH-secreting neuronal cell line -insulin maximally increases Egr-1 mRNA after 30 minutes of treatment and Egr-1 protein and GnRH mRNA after 60 minutes of treatment. Egr-1 small interfering RNA blocks the insulin-induced increase in GnRH promoter activity, measured as luciferase expression. Chromatin immunoprecipitation using Egr-1 antibody precipitates DNA in a proximal region of the GnRH promoter but not DNA in a distal region. Mutagenesis of a putative Egr-1 binding site within the proximal region blocks the insulin-induced increase in GnRH promoter activity. Thus, Egr-1 binds the GnRH promoter at a site between −67 and −76 bp from the transcriptional start site to mediate the insulin induced increase in GnRH gene transcription.

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“…These data suggest a mediatory role for PGE2 in TGF-α-stimulated GnRH secretion by GT1–7 cells. In contrast, IGF-I acts directly on GT1–7 cells, which also express IGF-I receptor [32]. Treatment of GT1–7 cells with IGF-I or IGF-II stimulated GnRH secretion by GT1–7 cells during the first 2 h of treatment [32].…”

Section: Discussionmentioning

confidence: 99%

“…GT1–7 cells were first grown at 37°C in a humidified atmosphere of 95% air and 5% CO 2 in 10% fetal bovine serum (FCS)-supplemented Dulbecco’s modified Eagle medium (DME), then cultured in serum-free medium containing glucose and penicillin/streptomycin as previously described by Anderson et al [32]. After 24 h in serum-free medium, GT1–7 cells were cultured for an additional 12 h in 100% astrocyte-conditioned media or control serum-free F12/DME media.…”

Section: Methodsmentioning

confidence: 99%

“…After 24 h in serum-free medium, GT1–7 cells were cultured for an additional 12 h in 100% astrocyte-conditioned media or control serum-free F12/DME media. Media were then collected, centrifuged, and stored at –20°C until analysis of GnRH concentrations by specific and sensitive RIA was performed as previously described by Anderson et al [32]. The sensitivity of assay was 0.9 pg, and the intra-assay and inter-assay coefficient of variations were 5 and 7%, respectively.…”

Section: Methodsmentioning

confidence: 99%

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A Role for Hypothalamic Astrocytes in Dehydroepiandrosterone and Estradiol Regulation of Gonadotropin-Releasing Hormone (GnRH) Release by GnRH Neurons

Zwain¹,

Arroyo²,

Amato³

et al. 2002

Neuroendocrinology

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Molecules of astrocyte origin influence gonadotropin-releasing hormone (GnRH) release and GnRH neuronal growth and differentiation. Furthermore, type 1 astrocytes express steroid receptors, presenting the possibility that steroid actions on GnRH neurons might occur via astrocytes. Utilizing GT1–7 cells, a GnRH-secreting cell line, the present study demonstrates that astrocytes mediate dehydroepiandrosterone (DHEA) or estradiol (E2) stimulated GnRH secretion. Conditioned media (CM) from astrocytes cultured for 48 h alone, with DHEA (DHEA-CM), or with E2 (E2-CM) were collected, treated with charcoal to remove steroids, and added to GT1–7 cells in culture for 12 h to test the effect on GnRH secretion. DHEA-CM and E2-CM stimulated GnRH secretion by GT1–7 cells by 4- and 3-fold, respectively. The effect of DHEA-CM on GnRH secretion by GT1–7 cells appears to be related to both DHEA and its metabolite, E2, since blocking the metabolism of DHEA into estrogen in the DHEA-treated astrocytes partially reversed the stimulatory effect of DHEA-CM. Addition of transforming growth factor (TGF)-β1-neutralizing antibody to the astrocyte cultures reversed the stimulatory effects of both DHEA-CM and E2-CM on GnRH secretion by GT1–7 cells, suggesting that TGF-β1 derived from astrocytes may be the principle mediator of E2 and DHEA effects. These data provide evidence for a novel mechanism by which circulating steroids and/or neurosteroids may modulate GnRH secretion.

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The Insulin-Like Growth Factor System in the GT1-7 GnRH Neuronal Cell Line

Cited by 38 publications

References 33 publications

Divergent roles of growth factors in the GnRH regulation of puberty in mice

Divergent roles of growth factors in the GnRH regulation of puberty in mice

Egr-1 binds the GnRH promoter to mediate the increase in gene expression by insulin

A Role for Hypothalamic Astrocytes in Dehydroepiandrosterone and Estradiol Regulation of Gonadotropin-Releasing Hormone (GnRH) Release by GnRH Neurons

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