Promoter Transgenics Reveal Multiple Gonadotropin-Releasing Hormone-I-Expressing Cell Populations of Different Embryological Origin in Mouse Brain

Skynner, Michael J.; Slater, Ruth; Sim, Joan A.; Allen, Nicholas Denby; Herbison, Allan E.

doi:10.1523/jneurosci.19-14-05955.1999

Cited by 128 publications

(102 citation statements)

References 37 publications

(52 reference statements)

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“…The distribution of GnRH neurons was the same as that reported previously in the mouse (Jennes and Stumpf, 1986;Skynner et al, 1999). The number of GnRH neurons detected within the rostral preoptic area was not influenced by estrogen treatment or different in males and females (male-vehicle, 17Ϯ1 GnRH neurons/ section; male-estrogen, 16Ϯ1; female-vehicle, 15Ϯ2; female-estrogen, 17Ϯ2).…”

Section: Creb and Pcreb In Gnrh Neuronssupporting

confidence: 83%

Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

Ábrahám

Herbison

2005

Neuroscience

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Abstract-Rapid effects of estrogen have now been identified throughout the brain but the extent to which these actions may be different in males and females is unknown. Previous work has shown that estrogen rapidly phosphorylates Ser 133 of cAMP responsive element binding protein (CREB) through a non-genomic mechanism. Using this indicator, we have examined here whether non-genomic estrogen actions occur in a sexually dimorphic manner within the adult brain. Male and female mice were gonadectomized and 3 weeks later treated with 17-␤-estradiol or vehicle for 1 h prior to perfusion fixation and subsequent CREB and phosphorylated CREB (pCREB) immunostaining of brain sections. The numbers of cells expressing CREB immunoreactivity were not altered by estrogen treatment or different in males and females in any of the brain regions examined. However, estrogen treatment significantly (P<0.05) increased pCREB-immunoreactive cell numbers in the medial preoptic area, ventrolateral division of the ventromedial nucleus, medial septum and CA1 region of the hippocampus of female mice. In contrast, estrogen increased pCREB levels in the medial septum and CA1 but not in the preoptic area or ventromedial nucleus of male mice. To evaluate the extent to which non-genomic estrogen actions may be sexually differentiated within a single neuronal phenotype, dual labeling immunocytochemistry was undertaken to evaluate the gonadotropin-releasing hormone ( A variety of neuronal circuits in the mammalian brain exhibit robust sex differences in structure and function (De Vries, 1990;Simerly, 2002). Hypothalamic regions such as the medial preoptic area (mPOA) and ventromedial nucleus (VMN) contain key sexually differentiated neuronal circuits responsible for controlling reproductive function (Pfaff et al., 1994;Flanagan-Cato, 2000;Simerly, 2002). For example, the GnRH neurons within the mPOA represent the final output neurons of the network involved in regulating gonadal function (Levine, 2003). Whereas estrogen stimulates a massive increment in GnRH secretion to induce ovulation in the female mammal, it has no similar effect in males (Herbison, 1998). In addition, clear sex differences have been observed in the effects of estrogen on networks involved in regulating male and female sexual behavior (Pfaff et al., 1994;Flanagan-Cato, 2000). Interestingly, these sexually differentiated actions of estrogen are not confined solely to circuits involved in the modulation of reproductive function but also exist within brain regions such as the hippocampus (Woolley, 2000;Leranth et al., 2003).The mechanisms underlying the sexually dimorphic effects of estrogen on brain function in the adult are unclear. As one possibility, estrogen may regulate different numbers or populations of cells within a specific brain region of males and females. This is likely to be the case for the sexually dimorphic nucleus of the preoptic area and the spinal nucleus of the bulbocavernosus in the rat (for review see Simerly, 2002) where major sex differences in neuronal n...

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Section: Creb and Pcreb In Gnrh Neuronssupporting

confidence: 83%

Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

Ábrahám

Herbison

2005

Neuroscience

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“…For example, we do not fully understand the roles of GnRH in the mammalian central nervous system. 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].…”

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

121

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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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“…Transgenic mice bearing a GnRH-lacZ reporter construct were found also found to express low levels of ␤-galactosidase in extra-hypothalamic regions of the brain, and further study demonstrated GnRH expression in these non-hypothalamic regions during normal embryological development (25). Alternatively, the lack of the 3Ј-sequences in the mGnRH-LUC construct may lead to aberrant regulation of the luciferase transgene so that luciferase activity persists in the absence of GnRH peptide.…”

Section: Figmentioning

confidence: 99%

Promoter Sequences Targeting Tissue-specific Gene Expression of Hypothalamic and Ovarian Gonadotropin-releasing Hormone in Vivo

Kim

Wolfe

Smith

et al. 2002

Journal of Biological Chemistry

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Molecular mechanisms directing tissue-specific expression of gonadotropin-releasing hormone (GnRH) are difficult to study due to the paucity and scattered distribution of GnRH neurons. To identify regions of the mouse GnRH (mGnRH) promoter that are critical for appropriate tissue-specific gene expression, we generated transgenic mice with fragments (؊3446/؉23 bp, ؊2078/؉23 bp, and ؊1005/؉28 bp) of mGnRH promoter fused to the luciferase reporter gene. The pattern of mGnRH promoter activity was assessed by measuring luciferase activity in tissue homogenates. All three 5-fragments of mGnRH promoter targeted hypothalamic expression of the luciferase transgene, but with the exception of the ovary, luciferase expression was absent in non-neural tissues. High levels of ovarian luciferase activity were observed in mice generated with both ؊2078 and ؊1005 bp of promoter. Our study is the first to define a region of the GnRH gene promoter that directs expression to both neural and non-neural tissues in vivo. We demonstrate that DNA sequences contained within the proximal ؊1005 bp of the mGnRH promoter are sufficient to direct mGnRH gene expression to both the ovary and hypothalamus. Our results also suggest that DNA sequences distal to ؊2078 bp mediate the repression of ovarian GnRH.

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Promoter Transgenics Reveal Multiple Gonadotropin-Releasing Hormone-I-Expressing Cell Populations of Different Embryological Origin in Mouse Brain

Cited by 128 publications

References 37 publications

Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

Major sex differences in non-genomic estrogen actions on intracellular signaling in mouse brain in vivo

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

Promoter Sequences Targeting Tissue-specific Gene Expression of Hypothalamic and Ovarian Gonadotropin-releasing Hormone in Vivo

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