What Nature's Knockout Teaches Us about GnRH Activity: Hypogonadal Mice and Neuronal Grafts

Gibson, M.E.; Wu, Tao; Miller, Gregory M.; Silverman, Ann‐Judith

doi:10.1006/hbeh.1997.1387

Cited by 35 publications

(14 citation statements)

References 55 publications

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“…Characterization of the reproductive phenotype of Six6-null males reveals a similar 84% decrease in GnRH neuron numbers and confirms previous studies showing that pulsatile secretion of LH in male mice is achievable with only a few GnRH neurons. Furthermore, our results support data that demonstrate a differential effect of reduced GnRH neuron numbers on plasma gonadotropin levels in males (Gibson et al, 1997; Herbison et al, 2008). Six6 KO males have a much greater reduction in serum FSH concentrations (~75%) than either LH or T (~35%), suggesting that a larger cohort of GnRH neurons is required to maintain normal levels of FSH in males.…”

Section: Discussionsupporting

confidence: 90%

Hypothalamic Dysregulation and Infertility in Mice Lacking the Homeodomain Protein Six6

Larder

Clark²,

Miller³

et al. 2011

J. Neurosci.

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The hypothalamus, pituitary, and gonads coordinate to direct the development and regulation of reproductive function in mammals. Control of the hypothalamic–pituitary– gonadal axis is dependent on correct migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus, followed by proper synthesis and pulsatile secretion of GnRH, functions absent in patients with hypogonadal hypogonadism. In this study, we identify sine oculis-related homeobox 6 (Six6) as a novel factor necessary for proper targeting of GnRH expression to the limited population of GnRH neurons within the adult mouse hypothalamus and demonstrate that it is required for proper reproductive function in both male and female mice. Female Six6-null mice exhibit a striking decrease in fertility, failing to progress through the estrous cycle normally, show any signs of successful ovulation, or produce litters. Although basal gonadotropin production in these mice is relatively normal, analysis of GnRH expression reveals a dramatic decrease in total GnRH neuron numbers. We show that expression of Six6 is dramatically increased during GnRH neuronal maturation and that overexpression of Six6 induces GnRH transcription in neuronal cells. Finally, we demonstrate that this induction in GnRH expression is mediated via binding of Six6 to evolutionarily conserved ATTA sites located within the GnRH proximal promoter. Together, these data indicate that Six6 plays an important role in the regulation of GnRH expression and hypothalamic control of fertility.

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Section: Discussionsupporting

confidence: 90%

Hypothalamic Dysregulation and Infertility in Mice Lacking the Homeodomain Protein Six6

Larder

Clark²,

Miller³

et al. 2011

J. Neurosci.

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“…It is well known that the physiological controls of reproduction and energy balance are closely intertwined, perhaps to maximize chances of individual survival and propagation of species. The GnRH neurons are a key element of the HPG axis; they integrate various internal homeostatic and external environmental signals and serve as the final pathway via which the brain controls fertility in all mammalian species; a lack of GnRH leads to infertility (61). GnRH neurons project to the median eminence and the released GnRH enhances pituitary gonadotropin secretion, which in turn release the sex steroids from the gonads.…”

Section: Discussionmentioning

confidence: 99%

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Dumalska²,

Morozova³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

107

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A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba 2؉ -sensitive K ؉ channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.fertility ͉ gonadotropins ͉ HPG axis ͉ obesity ͉ starvation N utritional status and availability of energy stores exert a profound impact on reproductive function (1-3). Reproduction is an expensive energy-consuming process, and thus it is important that puberty, pregnancy, and lactation occur only when metabolic fuel is available (4). Availability of metabolic fuel is conveyed to the brain by peripherally generated signals, such as leptin, insulin, and ghrelin, as well as by centrally released peptides such as neuropeptide Y, melanocortins, and melanin-concentrating hormone (MCH). One or more of these signals can directly or indirectly link energy balance with reproduction at one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. Thus, insulin and leptin may indirectly influence GnRH neurons (2, 5-7); leptin could regulate the HPG axis via kisspeptin-containing hypothalamic neurons (8, 9). Kisspeptin and its receptor are critical for reproduction (10-12); both kisspeptin and kisspeptin receptor knockout mice fail to enter puberty, and humans with loss of function mutations in the kisspeptin receptor exhibit hypogonadotropic hypogonadism and are infertile (13-15). Mechanisti...

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“…In vivo and in vitro studies in the rat hypothalamus (Sarkar and Fink, 1980; Spratt and Herbison, 1997) indicate that estrogen inhibits GnRH mRNA expression and that this effect is localized to the rostral preoptic area of the hypothalamus. The inhibitory effect of estrogen seems to involve different anatomical sites in the hypothalamus than those associated with the stimulatory effect of estrogen on GnRH (Shander and Barraclough, 1980; Wiegand et al, 1980; Wray et al, 1989; Gibson et al, 1997; Caraty et al, 1998), which had indicated that the inhibitory and stimulatory effects may occur independently from one another. Negative feedback was localized to the arcuate and median eminence of the medial basal hypothalamus in these studies while positive feedback was mapped to the preoptic and suprachiasmatic nucleus.…”

Section: Evidence For Regulation Of Gnrh Gene Expression By Estrogenmentioning

confidence: 99%

Estrogenic Regulation of the GnRH Neuron

Radovick

Levine

Wolfe³

2012

Front. Endocrin.

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Reproductive function is regulated by the secretion of luteinizing hormone (LH) and follicle-stimulating hormone from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex characteristics, gametogenesis, cellular function, and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common pathway for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about circadian, seasonal, behavioral, pheromonal, and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease, or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dramatic increase in GnRH secretion (Moenter et al., 1992; Xia et al., 1992; Clarke, 1993; Sisk et al., 2001). This is coupled with an increase in pituitary sensitivity to GnRH (Savoy-Moore et al., 1980; Turzillo et al., 1995), which produces the massive surge in secretion of LH that triggers ovulation. While feedback regulation of the axis in males is in part mediated by estrogen receptors (ER), there is not a clear consensus as to the relative role of ER versus AR signaling in males (Lindzey et al., 1998; Wersinger et al., 1999). Therefore, this review will focus on estrogenic signaling in the female.

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What Nature's Knockout Teaches Us about GnRH Activity: Hypogonadal Mice and Neuronal Grafts

Cited by 35 publications

References 55 publications

Hypothalamic Dysregulation and Infertility in Mice Lacking the Homeodomain Protein Six6

Hypothalamic Dysregulation and Infertility in Mice Lacking the Homeodomain Protein Six6

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Estrogenic Regulation of the GnRH Neuron

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