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Annjudith Silverman - One of the best experts on this subject based on the ideXlab platform.
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What Nature's Knockout Teaches Us about GnRH Activity: Hypogonadal Mice and Neuronal Grafts
Hormones and Behavior, 1997Co-Authors: Marie J Gibson, Gregory M Miller, T J Wu, Annjudith SilvermanAbstract:Abstract The Hypogonadal Mouse is one of “nature's knockouts,” bearing a specific deletion in the gene for gonadotropin-releasing hormone (GnRH), with the result that no GnRH peptide is detectable in the brain. The lack of reproductive development after birth provides an animal model that has proved fruitful in clarifying the role of GnRH in reproductive behavior and physiology. Behavioral studies with Hypogonadal mice convincingly demonstrate that although GnRH may facilitate the appearance of sexual behavior, this peptide is not essential for either male or female sexual behavior in the Mouse. Administration of GnRH to Hypogonadal mice with regimens mimicking GnRH pulsatility initiates reproductive development. Surprisingly, continuous exposure to GnRH stimulates remarkable ovarian and uterine growth and increased FSH release, although pituitary content of LH and FSH remains unchanged. In contrast, when brain grafts of normal fetal preoptic area (POA), containing GnRH cells, are implanted in the third ventricle of adult Hypogonadal mice, both pituitary and plasma gonadotropin levels increase. Grafted GnRH neurons innervate the median eminence of the host and support pulsatile LH secretion in the majority of animals with graft-associated gonadal development. Studies of Hypogonadal mice with POA grafts demonstrate that distinct components of reproductive function are dissociable: hosts may demonstrate reflex but not spontaneous ovulation; others may show positive but not negative feedback. Activation of grafted GnRH cells in response to sensory input to the host, as revealed in Fos expression studies, is an example of the integration of the graft with the host brain that underlies such capabilities. A goal of these studies is to elucidate the specific connectivity underlying discrete aspects of reproductive function.
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fos expression in grafted gonadotropin releasing hormone neurons in Hypogonadal Mouse mating and steroid induction
Journal of Neurobiology, 1996Co-Authors: T J Wu, Annjudith Silverman, M J GibsonAbstract:SUMMARY We used FOS expression, widely accepted as a marker for neuronal activation, to evaluate physiologically induced activation of gonadotropin-releasing hormone (GnRH) neurons within intraventricular preoptic area grafts in Hypogonadal (hpg) female mice. Hpg mice lack endogenous GnRH due to a mutated gene, but can respond to grafted GnRH neurons with reproductive development. The purpose of this study was to determine the degree to which the host brain regulates grafted GnRH neurons. FOS expression in grafted GnRH neurons was induced in progesterone-primed female mice paired with sexually active males. The degree of sexual activity did not affect the outcome, with 40.9 +- 12.2% of the grafted GnRH cells expressing FOS when male partners performed intromissions, and 47.5 f 10.2% when they also ejaculated. There was little or no FOS expression in the grafts of unprimed hpg mice paired with sexually active males, in unpaired mice primed with progesterone or sequential estradiol benzoate and progesterone, or in controls. The pattern of FOS expression in the brains of the female hpg mice engaged in mating behavior was similar to that reported in other species, with moderate to high expression in the medial preoptic area, ventromedial nucleus, and medial amygdala in females paired with males that ejaculated. The present results support the hypothesis that host-derived activation of grafted GnRH neurons underlies aspects of reproductive responses seen in hpg mice with grafts, and further, that at least a portion of the host-graft connectivity is steroid sensitive. o 1996
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Neuroendocrine brain grafts
Seminars in Neuroscience, 1993Co-Authors: Marie J Gibson, Annjudith SilvermanAbstract:Neuroendocrine grafts have been used to ameliorate symptoms associated with genetic or imposed deficiencies. In the course of these studies, it has become evident that the technique may be used to study some basic questions in neurobiology, including targeting, plasticity and integration of neurons. Among the genetic models employed, the Hypogonadal Mouse, deficient in gonadotropin-releasing hormone (GnRH), has provided an excellent opportunity to address certain of these issues. GnRH cells present in preoptic area grafts derived from normal mice show directed axonal outgrowth to the median eminence of the host, and GnRH neurons may migrate from the graft into the host hypothalamus. The adult host brain sends identified neuronal processes, into the graft and modulates physiological functioning of the grafted cells.
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gonadotropin releasing hormone gnrh neurons in the Hypogonadal Mouse elaborate normal projections despite their biosynthetic deficiency
Neuroscience Letters, 1993Co-Authors: Izhar Livne, Marie J Gibson, Annjudith SilvermanAbstract:Abstract This study was undertaken to determine whether gonadotropin-releasing hormone (GnRH) neurons in the mutant Hypogonadal (hpg) Mouse can establish axonal connections with their target despite their failure to synthesize and secrete the GnRH neuropeptide. Normal and hpg males received intraperitoneal injections of the retrograde tracer Fluoro-Gold. This tracer does not cross the blood-brain-barrier and hence is taken up only by neurons in the central nervous system whose axons terminate on fenestrated capillaries, such as the capillaries of the median eminence. The brains of the injected animals were processed for in situ hybridization to visualize GnRH transcribing cells. In 3 hpg males 64.1 ± 5.6% of GnRH transcribing cells contained Fluoro-Gold, while 55.8 ± 6.4% of the cells in 3 normal males had Fluoro-Gold. Thus, we have demonstrated that secretory-deficient GnRH neurons can establish axonal connections with their primary secretory target, the median eminence. We conclude that the capability of GnRH neurons to recognize and interact with their target is not dependent upon their neurosecretory function.
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functional gnrh neuronal transplants in the Hypogonadal Mouse
1992Co-Authors: Marie J Gibson, Youichi Saitoh, Gregory M Miller, Annjudith SilvermanAbstract:Transplantation of neuronal tissue containing GnRH cells into the brain of the mutant Hypogonadal Mouse has provided us with an important tool to study mechanisms of GnRH secretion. Lacking GnRH because of a deletion in the GnRH gene (1), the adult hpg Mouse has an undeveloped reproductive system (2), but responds to implantation of normal fetal or neonatal preoptic area tissue grafts into the third ventricle of the brain with reproductive development. GnRH cells survive within the grafts (Fig. 9.1a) and innervate the median eminence of the host brains (Fig. 9.1b). Both male (3, 4) and female (5) hpg mice with grafts (hpg/POA) increase pituitary gonadotropin production, which results in gonadal development.
H M Charlton - One of the best experts on this subject based on the ideXlab platform.
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effects of fsh on testicular mrna transcript levels in the Hypogonadal Mouse
Journal of Molecular Endocrinology, 2008Co-Authors: M H Abel, H M Charlton, D Baban, Peter J OshaughnessyAbstract:Follicle stimulating hormone (FSH) acts through the Sertoli cell to ensure normal testicular development and function. To identify transcriptional mechanisms through which FSH acts in the testis we have treated gonadotrophin-deficient Hypogonadal (hpg) mice with recombinant FSH and measured changes in testicular transcript levels using microarrays and real-time PCR 12, 24 and 72h after the start of treatment. Approximately 400 transcripts were significantly altered at each time point by FSH treatment. At 12h there was a clear increase in the levels of a number of transcripts known to be expressed in the Sertoli cells (eg Fabp5, Lgals1, Tesc, Scara5, Aqp5). Additionally, level of Leydig cell transcipts were also markedly increased (eg Ren1, Cyp17a1, Akr1b7, Star, Nr4a1). This was associated with a small but significant rise in testosterone at 24 and 72h. At 24h, androgen-dependent Sertoli cell transcripts were upregulated (eg Rhox5, Drd4, Spinlw1, Tubb3 and Tsx) and this trend continued up to 72h. Surprisingly, only 4 germ cell trancripts (Dkkl1, Hdc, Oct4 and 1700021K02Rik) were altered by FSH within the time-course of the experiment. Pathway analysis showed changes in cell cycle and cell proliferation pathways at all times and a general decline in transcripts related to formation and regulation of tight junctions. Results show FSH acts directly and indirectly to induce rapid changes in Sertoli cell and Leydig cell transcript levels in the hpg Mouse but that effects on germ cell development must occur over a longer time span.
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Hypogonadal Mouse a model to study the effects of the endogenous lack of gonadotropins on apoptosis
Biology of Reproduction, 2008Co-Authors: Oriane E Chausiaux, H M Charlton, M H Abel, Fiona O Baxter, Walid T Khaled, Peter J I Ellis, Nabeel A AffaraAbstract:Testicular apoptosis is involved in the regulation of germ cell numbers, allowing optimal sperm production. Apoptosis has been described to occur in response to the absence of hormonal stimulation of the testis. Here we investigate the effect of the physiological lack of gonadotropins from birth using the Hypogonadal (homozygous for the mutant allele Gnrh1 hpg ) Mouse as a model. We pursued a concerted strategy using microarray analysis and RT-PCR to assess transcript levels, TUNEL to quantify the incidence of apoptosis, and Western blotting to assess the respective contribution of the extrinsic and intrinsic apoptotic pathways. Our results indicate a large increase in apoptosis of both somatic and germ cell compartments in the hpg testis, affecting Sertoli cells as well as germ cells of all ages. We confirmed our observations of Sertoli cell apoptosis using anti-Mullerian inhibiting substance staining and staining for cleaved fodrin alpha. In the somatic compartment, apoptosis is primarily regulated via the membrane receptor (extrinsic) apoptotic pathway, while in the germ cell compartment, regulation occurs via both the mitochondrial (intrinsic) and membrane receptor (extrinsic) apoptotic pathways, the latter potentially in a stage-specific manner. This study is the first report of spermatogonial apoptosis in response to gonadotropin deficiency as well as the first report of Sertoli cell apoptosis in response to gonadotropin deficiency in the Mouse. apoptosis, follicle-stimulating hormone, gonadotropin-releasing hormone, Hpg, leutenizing hormone, sertoli cells, testis
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effects of fsh on leydig cell morphology and function in the Hypogonadal Mouse
Journal of Endocrinology, 1992Co-Authors: P J Oshaughnessy, M K Bennett, I S Scott, H M CharltonAbstract:: The Hypogonadal (hpg) Mouse has a congenital deficiency in gonadotrophin-releasing hormone and the gonads consequently lack exposure to endogenous gonadotrophins during development. To determine the effect of FSH on Leydig cell function in these animals adult hpg mice were injected twice daily with FSH (2 micrograms injections) or LH (40 ng injections, the presumed LH contamination of FSH used). Following FSH treatment there was a clear stimulation of the seminiferous epithelium and in animals injected with FSH plus [3H]thymidine, the incorporation of label was largely confined to the germ cells with no apparent uptake by the Sertoli cells. In FSH-treated testes the Leydig cells contained numerous large lipid droplets, similar to the unstimulated hpg testis. There was no evidence of the interstitial hyperplasia which is observed following injection of high doses of LH (2 micrograms twice daily). There was no change in basal androgen content of the testis in vivo following FSH treatment but injection of a maximal dose of human chorionic gonadotrophin (hCG), 1 h before death, markedly increased testicular androgen content only in the FSH-treated group. Testicular androgen production in vitro was significantly increased following FSH treatment both under basal conditions (FSH-treated, 17.4 pmol/testis; control, 1.46 pmol/testis) and during stimulation by hCG (FSH-treated, 940 pmol/testis; control, 81 pmol/testis). Associated with the increased androgen production following FSH treatment there were significant increases in the activities of three steroidogenic enzymes; cholesterol side-chain cleavage (186-fold increase over control), 17 alpha-hydroxylase (103-fold increase) and 17-ketosteroid reductase (177-fold increase).(ABSTRACT TRUNCATED AT 250 WORDS)
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Hypothalamic transplantation.
Ciba Foundation symposium, 1992Co-Authors: H M CharltonAbstract:Tissue transplantation aided in formulating the neurohumoral hypothesis of anterior pituitary function. The concept of a hypophysiotropic region within the hypothalamus stemmed from experiments in which pituitary tissue was transplanted into the brain. Restoration of aberrant function of the central nervous system by transplants has been reported in two neuroendocrine models: the antidiuretic hormone-deficient Brattleboro rat and the gonadotropin-releasing hormone-deficient Hypogonadal Mouse. Neural transplants into the Brattleboro rat result in the survival of axons containing antidiuretic hormone but reversal of the physiological defect has not been confirmed. In the Hypogonadal Mouse grafts of preoptic area tissue into the third ventricle have restored pituitary hormone synthesis and secretion and gonadal activity, leading to nearly normal reproductive function. The gonadotropin-releasing hormone axons specifically innervate the median eminence of the hypothalamus, their normal target, which raises interesting questions of neurobiological graft/host interactions. The hpg model has been used to investigate factors affecting graft survival; by suitable immunosuppression it has been possible to reverse the hypogonadism with grafts of rat preoptic area tissue. Perhaps the most dramatic recent development has been the restoration of circadian rhythmicity to suprachiasmatic nucleus-lesioned hamsters by grafts of similar tissue. The rhythmicity restored is typical of the donor tissue.
Marie J Gibson - One of the best experts on this subject based on the ideXlab platform.
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What Nature's Knockout Teaches Us about GnRH Activity: Hypogonadal Mice and Neuronal Grafts
Hormones and Behavior, 1997Co-Authors: Marie J Gibson, Gregory M Miller, T J Wu, Annjudith SilvermanAbstract:Abstract The Hypogonadal Mouse is one of “nature's knockouts,” bearing a specific deletion in the gene for gonadotropin-releasing hormone (GnRH), with the result that no GnRH peptide is detectable in the brain. The lack of reproductive development after birth provides an animal model that has proved fruitful in clarifying the role of GnRH in reproductive behavior and physiology. Behavioral studies with Hypogonadal mice convincingly demonstrate that although GnRH may facilitate the appearance of sexual behavior, this peptide is not essential for either male or female sexual behavior in the Mouse. Administration of GnRH to Hypogonadal mice with regimens mimicking GnRH pulsatility initiates reproductive development. Surprisingly, continuous exposure to GnRH stimulates remarkable ovarian and uterine growth and increased FSH release, although pituitary content of LH and FSH remains unchanged. In contrast, when brain grafts of normal fetal preoptic area (POA), containing GnRH cells, are implanted in the third ventricle of adult Hypogonadal mice, both pituitary and plasma gonadotropin levels increase. Grafted GnRH neurons innervate the median eminence of the host and support pulsatile LH secretion in the majority of animals with graft-associated gonadal development. Studies of Hypogonadal mice with POA grafts demonstrate that distinct components of reproductive function are dissociable: hosts may demonstrate reflex but not spontaneous ovulation; others may show positive but not negative feedback. Activation of grafted GnRH cells in response to sensory input to the host, as revealed in Fos expression studies, is an example of the integration of the graft with the host brain that underlies such capabilities. A goal of these studies is to elucidate the specific connectivity underlying discrete aspects of reproductive function.
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Neuroendocrine brain grafts
Seminars in Neuroscience, 1993Co-Authors: Marie J Gibson, Annjudith SilvermanAbstract:Neuroendocrine grafts have been used to ameliorate symptoms associated with genetic or imposed deficiencies. In the course of these studies, it has become evident that the technique may be used to study some basic questions in neurobiology, including targeting, plasticity and integration of neurons. Among the genetic models employed, the Hypogonadal Mouse, deficient in gonadotropin-releasing hormone (GnRH), has provided an excellent opportunity to address certain of these issues. GnRH cells present in preoptic area grafts derived from normal mice show directed axonal outgrowth to the median eminence of the host, and GnRH neurons may migrate from the graft into the host hypothalamus. The adult host brain sends identified neuronal processes, into the graft and modulates physiological functioning of the grafted cells.
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gonadotropin releasing hormone gnrh neurons in the Hypogonadal Mouse elaborate normal projections despite their biosynthetic deficiency
Neuroscience Letters, 1993Co-Authors: Izhar Livne, Marie J Gibson, Annjudith SilvermanAbstract:Abstract This study was undertaken to determine whether gonadotropin-releasing hormone (GnRH) neurons in the mutant Hypogonadal (hpg) Mouse can establish axonal connections with their target despite their failure to synthesize and secrete the GnRH neuropeptide. Normal and hpg males received intraperitoneal injections of the retrograde tracer Fluoro-Gold. This tracer does not cross the blood-brain-barrier and hence is taken up only by neurons in the central nervous system whose axons terminate on fenestrated capillaries, such as the capillaries of the median eminence. The brains of the injected animals were processed for in situ hybridization to visualize GnRH transcribing cells. In 3 hpg males 64.1 ± 5.6% of GnRH transcribing cells contained Fluoro-Gold, while 55.8 ± 6.4% of the cells in 3 normal males had Fluoro-Gold. Thus, we have demonstrated that secretory-deficient GnRH neurons can establish axonal connections with their primary secretory target, the median eminence. We conclude that the capability of GnRH neurons to recognize and interact with their target is not dependent upon their neurosecretory function.
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functional gnrh neuronal transplants in the Hypogonadal Mouse
1992Co-Authors: Marie J Gibson, Youichi Saitoh, Gregory M Miller, Annjudith SilvermanAbstract:Transplantation of neuronal tissue containing GnRH cells into the brain of the mutant Hypogonadal Mouse has provided us with an important tool to study mechanisms of GnRH secretion. Lacking GnRH because of a deletion in the GnRH gene (1), the adult hpg Mouse has an undeveloped reproductive system (2), but responds to implantation of normal fetal or neonatal preoptic area tissue grafts into the third ventricle of the brain with reproductive development. GnRH cells survive within the grafts (Fig. 9.1a) and innervate the median eminence of the host brains (Fig. 9.1b). Both male (3, 4) and female (5) hpg mice with grafts (hpg/POA) increase pituitary gonadotropin production, which results in gonadal development.
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Hypothalamic transplantation repair of reproductive defects in Hypogonadal mice
Trends in Endocrinology and Metabolism, 1990Co-Authors: Annjudith Silverman, Marie J GibsonAbstract:Abstract The defect of the Hypogonadal Mouse, resulting in infantile reproductive organs and severely reduced gonadotropin levels, is due to a truncation of the gene encoding for preprogonadotropinreleasing hormone. The Hypogonadal Mouse bearing a graft containing normal gonadotropin-releasing hormone neurons may show testicular development, seminal vesicle growth, and increased gonadotropin production in males. Normalization of gonadotropin levels in females is frequently associated with the capacity for a reflex ovulation followed by pregnancy and bearing of live young. All of these phenomena are dependent on the outgrowth of gonadotropin-releasing hormone axons from the graft to the host median eminence and the hypophysial portal capillaries.
Izhar Livne - One of the best experts on this subject based on the ideXlab platform.
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gonadotropin releasing hormone gnrh neurons in the Hypogonadal Mouse elaborate normal projections despite their biosynthetic deficiency
Neuroscience Letters, 1993Co-Authors: Izhar Livne, Marie J Gibson, Annjudith SilvermanAbstract:Abstract This study was undertaken to determine whether gonadotropin-releasing hormone (GnRH) neurons in the mutant Hypogonadal (hpg) Mouse can establish axonal connections with their target despite their failure to synthesize and secrete the GnRH neuropeptide. Normal and hpg males received intraperitoneal injections of the retrograde tracer Fluoro-Gold. This tracer does not cross the blood-brain-barrier and hence is taken up only by neurons in the central nervous system whose axons terminate on fenestrated capillaries, such as the capillaries of the median eminence. The brains of the injected animals were processed for in situ hybridization to visualize GnRH transcribing cells. In 3 hpg males 64.1 ± 5.6% of GnRH transcribing cells contained Fluoro-Gold, while 55.8 ± 6.4% of the cells in 3 normal males had Fluoro-Gold. Thus, we have demonstrated that secretory-deficient GnRH neurons can establish axonal connections with their primary secretory target, the median eminence. We conclude that the capability of GnRH neurons to recognize and interact with their target is not dependent upon their neurosecretory function.
M H Abel - One of the best experts on this subject based on the ideXlab platform.
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effects of fsh on testicular mrna transcript levels in the Hypogonadal Mouse
Journal of Molecular Endocrinology, 2008Co-Authors: M H Abel, H M Charlton, D Baban, Peter J OshaughnessyAbstract:Follicle stimulating hormone (FSH) acts through the Sertoli cell to ensure normal testicular development and function. To identify transcriptional mechanisms through which FSH acts in the testis we have treated gonadotrophin-deficient Hypogonadal (hpg) mice with recombinant FSH and measured changes in testicular transcript levels using microarrays and real-time PCR 12, 24 and 72h after the start of treatment. Approximately 400 transcripts were significantly altered at each time point by FSH treatment. At 12h there was a clear increase in the levels of a number of transcripts known to be expressed in the Sertoli cells (eg Fabp5, Lgals1, Tesc, Scara5, Aqp5). Additionally, level of Leydig cell transcipts were also markedly increased (eg Ren1, Cyp17a1, Akr1b7, Star, Nr4a1). This was associated with a small but significant rise in testosterone at 24 and 72h. At 24h, androgen-dependent Sertoli cell transcripts were upregulated (eg Rhox5, Drd4, Spinlw1, Tubb3 and Tsx) and this trend continued up to 72h. Surprisingly, only 4 germ cell trancripts (Dkkl1, Hdc, Oct4 and 1700021K02Rik) were altered by FSH within the time-course of the experiment. Pathway analysis showed changes in cell cycle and cell proliferation pathways at all times and a general decline in transcripts related to formation and regulation of tight junctions. Results show FSH acts directly and indirectly to induce rapid changes in Sertoli cell and Leydig cell transcript levels in the hpg Mouse but that effects on germ cell development must occur over a longer time span.
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Hypogonadal Mouse a model to study the effects of the endogenous lack of gonadotropins on apoptosis
Biology of Reproduction, 2008Co-Authors: Oriane E Chausiaux, H M Charlton, M H Abel, Fiona O Baxter, Walid T Khaled, Peter J I Ellis, Nabeel A AffaraAbstract:Testicular apoptosis is involved in the regulation of germ cell numbers, allowing optimal sperm production. Apoptosis has been described to occur in response to the absence of hormonal stimulation of the testis. Here we investigate the effect of the physiological lack of gonadotropins from birth using the Hypogonadal (homozygous for the mutant allele Gnrh1 hpg ) Mouse as a model. We pursued a concerted strategy using microarray analysis and RT-PCR to assess transcript levels, TUNEL to quantify the incidence of apoptosis, and Western blotting to assess the respective contribution of the extrinsic and intrinsic apoptotic pathways. Our results indicate a large increase in apoptosis of both somatic and germ cell compartments in the hpg testis, affecting Sertoli cells as well as germ cells of all ages. We confirmed our observations of Sertoli cell apoptosis using anti-Mullerian inhibiting substance staining and staining for cleaved fodrin alpha. In the somatic compartment, apoptosis is primarily regulated via the membrane receptor (extrinsic) apoptotic pathway, while in the germ cell compartment, regulation occurs via both the mitochondrial (intrinsic) and membrane receptor (extrinsic) apoptotic pathways, the latter potentially in a stage-specific manner. This study is the first report of spermatogonial apoptosis in response to gonadotropin deficiency as well as the first report of Sertoli cell apoptosis in response to gonadotropin deficiency in the Mouse. apoptosis, follicle-stimulating hormone, gonadotropin-releasing hormone, Hpg, leutenizing hormone, sertoli cells, testis