Immortalization of hypothalamic GnRH by genetically targeted tumorigenesis

Mellon, Pamela L.; Windle, Jolene J.; Goldsmith, Paul C.; Padula, Cheryl A.; Roberts, James L.; Weiner, Richard I.

doi:10.1016/0896-6273(90)90028-e

Cited by 921 publications

(610 citation statements)

References 44 publications

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“…Although relatively few studies have been performed, most show effects of endocrine disrupting chemicals, both in vitro and in vivo, on GnRH functional properties. In the hypothalamic GT1-7 GnRH cell line [100], polychlorinated biphenyls [65] and organochlorine pesticides such as methoxychlor and chlorpyrifos [61] have significant effects on GnRH gene expression, GnRH peptide release, and GT1-7 cell morphology. GnRH neurons in vivo are also affected by phytoestrogens such as coumestrol [99,171] and industrial contaminants, fungicides, and pesticides [17,59], as manifested by alterations in pulsatile GnRH/LH release, GnRH gene expression, and GnRH cell numbers.…”

Section: Effects Of Edcs On Hypothalamic Gnrh Neuronsmentioning

confidence: 99%

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Gore¹

2008

Frontiers in Neuroendocrinology

230

122

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The ability of a species to reproduce successfully requires the careful orchestration of developmental processes during critical time points, particularly the late embryonic and early postnatal periods. This article begins with a brief presentation of the evidence for how gonadal steroid hormones exert these imprinting effects upon the morphology of sexually differentiated hypothalamic brain regions, the mechanisms underlying these effects, and their implications in adulthood. Then, I review the evidence that aberrant exposure to hormonally-active substances such as exogenous endocrine-disrupting chemicals (EDCs), may result in improper hypothalamic programming, thereby decreasing reproductive success in adulthood. The field of endocrine disruption has shed new light on the discipline of basic reproductive neuroendocrinology through studies on how early life exposures to EDCs may alter gene expression via non-genomic, epigenetic mechanisms, including DNA methylation and histone acetylation. Importantly, these effects may be transmitted to future generations if the germline is affected via transgenerational, epigenetic actions. By understanding the mechanisms by which natural hormones and xenobiotics affect reproductive neuroendocrine systems, we will gain a better understanding of normal developmental processes, as well as to develop the potential ability to intervene when development is disrupted.

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Section: Effects Of Edcs On Hypothalamic Gnrh Neuronsmentioning

confidence: 99%

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Gore¹

2008

Frontiers in Neuroendocrinology

230

122

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“…Some detailed mapping and functional analyses of GnRH I and GnRH II neurons have been performed in mammals [28,29,131,145]. However, the action of GnRH on GnRH neurons or their neighboring cells has not been characterized in great depth, although several model cell lines, derived from mouse hypothalamic GnRH neurons, have provided the foundations for further functional studies [84,119]. More recently, the role of the metastin/kisspeptin receptor (gpr54) in influencing GnRH neuron function has been elucidated [30,85,117,138], but how mammalian GnRH I and GnRH II and the type I or type II GnRH receptors integrate into the complexity of neuronal function, in both males and females, still requires further elaboration.…”

Section: Potential Functions Of Gnrh In Mammalsmentioning

confidence: 99%

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

Millar

Pawson

Morgan

et al. 2008

Frontiers in Neuroendocrinology

122

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Geoffrey Wingfield Harris' demonstration of hypothalamic hormones regulating pituitary function led to their structural identification and therapeutic utilization in a wide spectrum of diseases. Amongst these, Gonadotropin Releasing Hormone (GnRH) and its analogs are widely employed in modulating gonadotropin and sex steroid secretion to treat infertility, precocious puberty and many hormone-dependent diseases including endometriosis, uterine fibroids and prostatic cancer. While these effects are all mediated via modulation of the pituitary gonadotrope GnRH receptor and the G q signaling pathway, it has become increasingly apparent that GnRH regulates many extrapituitary cells in the nervous system and periphery. This review focuses on two such examples, namely GnRH analog effects on reproductive behaviors and GnRH analog effects on the inhibition of cancer cell growth. For both effects the relative activities of a range of GnRH analogs is distinctly different from their effects on the pituitary gonadotrope and different signaling pathways are utilized. As there is only a single functional GnRH receptor type in man we have proposed that the GnRH receptor can assume different conformations which have different selectivity for GnRH analogs and intracellular signaling proteins complexes. This ligand-induced selective-signaling recruits certain pathways while by-passing others and has implications in developing more selective GnRH analogs for highly specific therapeutic intervention.

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“…GT1-7 clonal cells produce and release the gonadotropin-releasing hormone (GnRH) [26]. They also express CB1Rs and are able to synthesize and release endocannabinoids [27].…”

Section: Introductionmentioning

confidence: 99%

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

et al. 2009

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a b s t r a c tUsing immortalized hypothalamic GT1-7 neurons, which express the CB1 cannabinoid receptor (CB1R) and three Ca 2+ channel types (T, R and L), we found that the CB1R agonist WIN 55,212-2 inhibited the voltage-gated Ca 2+ currents by about 35%. The inhibition by WIN 55,212-2 (10 M) was reversible and prevented by nifedipine (3 M), suggesting a selective action on L-type Ca 2+ channels (LTCCs). WIN 55,212-2 action exhibited all the features of voltage-independent Ca 2+ channel modulation: (1) no changes of the activation kinetics, (2) equal depressive action at all potentials and (3) no facilitation following strong prepulses. At variance with WIN 55,212-2, the CB1R inverse agonist AM-251 (10 M) caused 20% increase of Ca 2+ currents. The inhibition of LTCCs by WIN 55,212-2 was prevented by overnight PTX-incubation and by intracellular perfusion with GDP-␤-S. The latter caused also a 20% Ca 2+ current up-regulation. WIN 55,212-2 action was also prevented by application of the PKA-blocker H89 or by loading the neurons with 8-CPT-cAMP. Our results suggest that LTCCs in GT1-7 neurons are partially inhibited at rest due to a constitutive CB1R activity removed by AM-251 and GDP-␤-S. Activation of CB1R via PTX-sensitive G proteins and cAMP/PKA pathway selectively depresses LTCCs that critically control the synchronized spontaneous firing and pulsatile release of gonadotropin-releasing hormone in GT1-7 neurons.

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Immortalization of hypothalamic GnRH by genetically targeted tumorigenesis

Cited by 921 publications

References 44 publications

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Developmental programming and endocrine disruptor effects on reproductive neuroendocrine systems

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

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