Journal articles on the topic 'Mice Reproduction Regulation'
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1
Rollo, C. D., J. Rintoul, and L. J. Kajiura. "Lifetime reproduction of giant transgenic mice: the energy stress paradigm." Canadian Journal of Zoology 75, no. 8 (August 1, 1997): 1336–45. http://dx.doi.org/10.1139/z97-758.
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Lifetime reproduction of female transgenic rat growth hormone (TRrGH) mice and their normal siblings was evaluated on a high-protein (38%) diet, a standard diet (23% protein), and the standard diet supplemented with sucrose cubes. Compared with those on the standard diet, normal mice fed the high-protein diet showed significant increases in litter size, number of litters, and lifetime fecundity. Number of litters and lifetime fecundity were also enhanced in normal mice fed sucrose. TRrGH mice showed no significant improvements in reproduction on the high-protein diet, but they were significantly smaller. Sucrose dramatically improved reproduction of TRrGH mice, with no reduction in mature mass. The percentage of fertile TRrGH mice increased from 45% on standard chow to 71% with sucrose. The number and size of litters of TRrGH mice also significantly increased with sucrose, mean lifetime fecundity doubling from 9 pups on standard food to 18 pups on sucrose. However, TRrGH mice did not attain the reproductive success of normal mice on any diet. These results suggest that TRrGH mice are energetically stressed by enforced channelling of energy into growth. An immense literature addresses infertility due to energy limitation and stress generally. We synthesize these aspects with growth hormone transgenesis to derive an integrated view of neuroendocrine energy regulation relevant to restoring fertility of transgenic GH animals.
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De Bond, Julie-Ann P., and Jeremy T. Smith. "Kisspeptin and energy balance in reproduction." REPRODUCTION 147, no. 3 (March 2014): R53—R63. http://dx.doi.org/10.1530/rep-13-0509.
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Kisspeptin is vital for the neuroendocrine regulation of GNRH secretion. Kisspeptin neurons are now recognized as a central pathway responsible for conveying key homeostatic information to GNRH neurons. This pathway is likely to mediate the well-established link between energy balance and reproductive function. Thus, in states of severely altered energy balance (either negative or positive), fertility is compromised, as isKiss1expression in the arcuate nucleus. A number of metabolic modulators have been proposed as regulators of kisspeptin neurons including leptin, ghrelin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY). Whether these regulate kisspeptin neurons directly or indirectly will be discussed. Moreover, whether the stimulatory role of leptin on reproduction is mediated by kisspeptin directly will be questioned. Furthermore, in addition to being expressed in GNRH neurons, the kisspeptin receptor (Kiss1r) is also expressed in other areas of the brain, as well as in the periphery, suggesting alternative roles for kisspeptin signaling outside of reproduction. Interestingly, kisspeptin neurons are anatomically linked to, and can directly excite, anorexigenic POMC neurons and indirectly inhibit orexigenic NPY neurons. Thus, kisspeptin may have a direct role in regulating energy balance. Although data fromKiss1rknockout and WT mice found no differences in body weight, recent data indicate that kisspeptin may still play a role in food intake and glucose homeostasis. Thus, in addition to regulating reproduction, and mediating the effect of energy balance on reproductive function, kisspeptin signaling may also be a direct regulator of metabolism.
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Thornton, Janice E., Clement C. Cheung, Donald K. Clifton, and Robert A. Steiner. "Regulation of Hypothalamic Proopiomelanocortin mRNA by Leptin in ob/ob Mice." Endocrinology 138, no. 11 (November 1, 1997): 5063–66. http://dx.doi.org/10.1210/endo.138.11.5651.
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The hormone leptin acts on the brain to regulate feeding, metabolism, and reproduction; however, its cellular targets and molecular mechanisms of action remain to be fully elucidated. The melanocortins, which are derived from the precursor proopiomelanocortin (POMC), are also implicated in the physiological regulation of body weight. POMC-containing neurons express the leptin receptor, and thus it is conceivable that the POMC gene itself may be part of the signaling pathway involved in leptin’s action on the brain. Using in situ hybridization and computerized image analysis, we tested the hypothesis that the POMC gene is a target for regulation by leptin by comparing cellular levels of POMC mRNA in the hypothalamus among groups of leptin-deficient (ob/ob) mice, leptin-treated ob/ob mice, and wild-type controls. POMC mRNA levels were significantly reduced throughout the arcuate nucleus in vehicle-treated ob/ob mice relative to wild-type controls, whereas POMC mRNA levels in leptin-treated ob/ob mice were indistinguishable from wild-type controls. These observations suggest that one or more products of POMC serve as an integrative link between leptin and the central mechanisms governing body weight regulation and reproduction.
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Gowri, P. Mangala, Surojeet Sengupta, Suzanne Bertera, and Benita S. Katzenellenbogen. "Lipin1 Regulation by Estrogen in Uterus and Liver: Implications for Diabetes and Fertility." Endocrinology 148, no. 8 (August 1, 2007): 3685–93. http://dx.doi.org/10.1210/en.2006-1728.
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Estrogens are essential for fertility and also have important effects on regulation of adiposity and the euglycemic state. We report here that lipin1, a candidate gene for lipodystrophy and obesity that is a phosphatidic acid phosphatase critical in regulation of cellular levels of diacylglycerol and triacylglycerol and a key regulator of lipid utilization, is rapidly and robustly down-regulated in the uterus by estradiol via the estrogen receptor. Lipin1 is expressed predominantly in the uterine luminal and glandular epithelium, and during the estrous cycle, lipin1 is lowest when blood levels of estrogen are highest. Lipin1 is expressed throughout all cells in the liver of ovariectomized female mice, and a sustained down-regulation is observed at the mRNA, protein and immunohistochemical levels after estrogen administration. Because the coupling of proper energy use and availability is central to reproduction, we also investigated expression of lipin1 in the uterus and liver of several mouse models of diabetes. Nonobese diabetic (NOD) mice, which have high blood levels of estrogen and impaired fertility, were severely deficient in lipin1 in the uterus and liver, which, interestingly, could be restored by insulin treatment. By contrast, nonobese diabetic/severe combined immunodeficient (NOD-SCID) mice, which do not develop diabetes, showed normal levels of lipin1. Our findings of lipin1 regulation by estrogen in two key target organs suggest a new role for this lipid-regulating phosphatase not only in central metabolic regulation but also in uterine function and reproductive biology. Estrogen regulation of lipin1 may provide a mechanistic link between estrogens, lipid metabolism, and lipid signaling.
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Oakley, Amy E., Donald K. Clifton, and Robert A. Steiner. "Kisspeptin Signaling in the Brain." Endocrine Reviews 30, no. 6 (October 1, 2009): 713–43. http://dx.doi.org/10.1210/er.2009-0005.
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Abstract Kisspeptin (a product of the Kiss1 gene) and its receptor (GPR54 or Kiss1r) have emerged as key players in the regulation of reproduction. Mutations in humans or genetically targeted deletions in mice of either Kiss1 or Kiss1r cause profound hypogonadotropic hypogonadism. Neurons that express Kiss1/kisspeptin are found in discrete nuclei in the hypothalamus, as well as other brain regions in many vertebrates, and their distribution, regulation, and function varies widely across species. Kisspeptin neurons directly innervate and stimulate GnRH neurons, which are the final common pathway through which the brain regulates reproduction. Kisspeptin neurons are sexually differentiated with respect to cell number and transcriptional activity in certain brain nuclei, and some kisspeptin neurons express other cotransmitters, including dynorphin and neurokinin B (whose physiological significance is unknown). Kisspeptin neurons express the estrogen receptor and the androgen receptor, and these cells are direct targets for the action of gonadal steroids in both male and female animals. Kisspeptin signaling in the brain has been implicated in mediating the negative feedback action of sex steroids on gonadotropin secretion, generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation. Kisspeptin signaling may also serve diverse functions outside of the classical realm of reproductive neuroendocrinology, including the regulation of metastasis in certain cancers, vascular dynamics, placental physiology, and perhaps even higher-order brain function.
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Hu, Hanyang, Xing Lu, Xiang Cen, Xiaohua Chen, Feng Li, and Shan Zhong. "RNA-Seq Identifies Key Reproductive Gene Expression Alterations in Response to Cadmium Exposure." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/529271.
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Cadmium is a common toxicant that is detrimental to many tissues. Although a number of transcriptional signatures have been revealed in different tissues after cadmium treatment, the genes involved in the cadmium caused male reproductive toxicity, and the underlying molecular mechanism remains unclear. Here we observed that the mice treated with different amount of cadmium in their rodent chow for six months exhibited reduced serum testosterone. We then performed RNA-seq to comprehensively investigate the mice testicular transcriptome to further elucidate the mechanism. Our results showed that hundreds of genes expression altered significantly in response to cadmium treatment. In particular, we found several transcriptional signatures closely related to the biological processes of regulation of hormone, gamete generation, and sexual reproduction, respectively. The expression of several testosterone synthetic key enzyme genes, such as Star, Cyp11a1, and Cyp17a1, were inhibited by the cadmium exposure. For better understanding of the cadmium-mediated transcriptional regulatory mechanism of the genes, we computationally analyzed the transcription factors binding sites and the mircoRNAs targets of the differentially expressed genes. Our findings suggest that the reproductive toxicity by cadmium exposure is implicated in multiple layers of deregulation of several biological processes and transcriptional regulation in mice.
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Taylor, Hugh S., and Xiaolan Fei. "Emx2 Regulates Mammalian Reproduction by Altering Endometrial Cell Proliferation." Molecular Endocrinology 19, no. 11 (November 1, 2005): 2839–46. http://dx.doi.org/10.1210/me.2005-0130.
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Abstract The molecular mechanisms that underlie embryo implantation are poorly understood. Under the control of sex steroids, uterine endometrium undergoes tremendous, yet tightly controlled, proliferation in each estrous cycle to facilitate implantation; disorders of endometrial proliferation underlie several uterine diseases. We have previously identified the Emx2 gene as a transcriptional target of HOXA10 regulation in the reproductive tract. Here we report the function of Emx2 in murine implantation and regulation of endometrial proliferation. We transfected mice on d 2 post coitus with pcDNA3.1/Emx2, Emx2 antisense, or respective controls consisting of empty pcDNA3.1 or a random order oligonucleotide by intrauterine lipofection. Increased expression of Emx2 reduced average implantation rate by approximately 40% (P = 0.00006) resulting in an average number of implanted embryos per litter of 13.7 in the control group to 8.2 in the pcDNA3.1/Emx2-treated group. Neither treatment altered the number of mice attaining pregnancy with at least one embryo. Decreased Emx2 expression did not alter litter size. Neither treatment affected the birth weight of the pups. To elucidate potential mechanisms through which Emx2-regulated reproduction, markers of endometrial differentiation, proliferation, and apoptosis were assessed. Increased Emx2 expression significantly decreased endometrial cell proliferating cell nuclear antigen expression and 5′-bromo-2′ deoxyuridine incorporation. Markers of stromal cell differentiation (IGF binding protein-1, prolactin), epithelial differentiation (calcitonin), and apoptosis (activated caspase3) were unchanged. In human endometrial epithelial cells in vitro, Emx2 reduced cell number indicating diminished proliferation. Emx2 controls mammalian reproduction by adjusting endometrial cell proliferation without effecting differentiation. Regulated uterine Emx2 expression is necessary during reproduction for maximal implantation and litter size.
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Martin, J. Ryan, Sarah B. Lieber, James McGrath, Marya Shanabrough, Tamas L. Horvath, and Hugh S. Taylor. "Maternal Ghrelin Deficiency Compromises Reproduction in Female Progeny through Altered Uterine Developmental Programming." Endocrinology 152, no. 5 (February 15, 2011): 2060–66. http://dx.doi.org/10.1210/en.2010-1485.
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Ghrelin has a well-known role in the regulation of appetite, satiety, energy metabolism, and reproduction; however ghrelin has not been implicated in reproductive tract development. We examined the effect of ghrelin deficiency on the developmental programming of female fertility. We observed that female wild-type mice born of ghrelin heterozygote dams (i.e. exposed in utero to ghrelin deficiency) had diminished fertility and produced smaller litters. We demonstrate that exposure to in utero ghrelin deficiency led to altered developmental programming of the reproductive tract. The number of ovarian follicles, corpora lutea, and embryos produced were identical in both exposed and unexposed mice. However wild-type embryos transferred to uteri of mice exposed to in utero ghrelin deficiency had a 60% reduction in the rate of embryo implantation compared with those transferred to wild-type unexposed uteri. We identified significant alterations in the uterine expression of four genes critical for implantation and a defect in uterine endometrial proliferation. Taken together, these results demonstrate that the mechanism of subfertility was abnormal endometrial function. In utero exposure to decreased levels of ghrelin led to defects in developmental programming of the uterus and subsequent subfertility in wild-type offspring.
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Klenke, Ulrike, Carol Taylor-Burds, and Susan Wray. "Metabolic Influences on Reproduction: Adiponectin Attenuates GnRH Neuronal Activity in Female Mice." Endocrinology 155, no. 5 (May 1, 2014): 1851–63. http://dx.doi.org/10.1210/en.2013-1677.
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Metabolic dysfunctions are often linked to reproductive abnormalities. Adiponectin (ADP), a peripheral hormone secreted by white adipose tissue, is important in energy homeostasis and appetite regulation. GnRH neurons are integral components of the reproductive axis, controlling synthesis, and release of gonadotropins. This report examined whether ADP can directly act on GnRH neurons. Double-label immunofluorescence on brain sections from adult female revealed that a subpopulation of GnRH neurons express ADP receptor (AdipoR)2. GnRH/AdipoR2+ cells were distributed throughout the forebrain. To determine the influence of ADP on GnRH neuronal activity and the signal transduction pathway of AdipoR2, GnRH neurons maintained in explants were assayed using whole-cell patch clamping and calcium imaging. This mouse model system circumvents the dispersed distribution of GnRH neurons within the forebrain, making analysis of large numbers of GnRH cells possible. Single-cell PCR analysis and immunocytochemistry confirmed the presence of AdipoR2 in GnRH neurons in explants. Functional analysis revealed 20% of the total GnRH population responded to ADP, exhibiting hyperpolarization or decreased calcium oscillations. Perturbation studies revealed that ADP activates AMP kinase via the protein kinase Cζ/liver kinase B1 pathway. The modulation of GnRH neuronal activity by ADP demonstrated in this report directly links energy balance to neurons controlling reproduction.
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Han, Gwidong, Seong-Hyeon Hong, Seung-Jae Lee, Seung-Pyo Hong, and Chunghee Cho. "Transcriptome Analysis of Testicular Aging in Mice." Cells 10, no. 11 (October 26, 2021): 2895. http://dx.doi.org/10.3390/cells10112895.
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Male reproductive aging, or andropause, is associated with gradual age-related changes in testicular properties, sperm production, and erectile function. The testis, which is the primary male reproductive organ, produces sperm and androgens. To understand the transcriptional changes underlying male reproductive aging, we performed transcriptome analysis of aging testes in mice. A total of 31,386 mRNAs and 9387 long non-coding RNAs (lncRNAs) were identified in the mouse testes of diverse age groups (3, 6, 12, and 18 months old) by total RNA sequencing. Of them, 1571 mRNAs and 715 lncRNAs exhibited changes in their levels during testicular aging. Most of these aging-related transcripts exhibited slight and continuous expression changes during aging, whereas some (9.6%) showed larger expression changes. The aging-related transcripts could be classified into diverse expression patterns, in which the transcripts changed mainly at 3–6 months or at 12–18 months. Our subsequent in silico analysis provided insight into the potential features of testicular aging-related mRNAs and lncRNAs. We identified testis-specific aging-related transcripts (121 mRNAs and 25 lncRNAs) by comparison with a known testis-specific transcript profile, and then predicted the potential reproduction-related functions of the mRNAs. By selecting transcripts that are altered only between 3 and 18 months, we identified 46 mRNAs and 34 lncRNAs that are stringently related to the terminal stage of male reproductive aging. Some of these mRNAs were related to hormonal regulation. Finally, our in silico analysis of the 34 aging-related lncRNAs revealed that they co-localized with 19 testis-expressed protein-coding genes, 13 of which are considered to show testis-specific or -predominant expression. These nearby genes could be potential targets of cis-regulation by the aging-related lncRNAs. Collectively, our results identify a number of testicular aging-related mRNAs and lncRNAs in mice and provide a basis for the future investigation of these transcripts in the context of aging-associated testicular dysfunction.
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Choi, Irene, Emily Rickert, Marina Fernandez, and Nicholas J. G. Webster. "SIRT1 in Astrocytes Regulates Glucose Metabolism and Reproductive Function." Endocrinology 160, no. 6 (April 25, 2019): 1547–60. http://dx.doi.org/10.1210/en.2019-00223.
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Abstract Sirtuin 1 (Sirt1) is an NAD-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, evidence suggests that SIRT1 in neurons plays a role in the central regulation of energy balance and reproduction, but no studies have addressed the contribution of astrocytes. We show here that overexpression of SIRT1 in astrocytes causes markedly increased food intake, body weight gain, and glucose intolerance, but expression of a deacetylase-deficient SIRT1 mutant decreases food intake and body weight and improves glucose tolerance, particularly in female mice. Paradoxically, the effect of these SIRT1 mutants on insulin tolerance was reversed, with overexpression showing greater insulin sensitivity. The mice overexpressing SIRT1 were more active, generated more heat, and had elevated oxygen consumption, possibly in compensation for the increased food intake. The female overexpressing mice were also more sensitive to diet-induced obesity. Reproductively, the mice expressing the deacetylase-deficient SIRT1 mutant had impaired estrous cycles, decreased LH surges, and fewer corpora lutea, indicating decreased ovulation. The GnRH neurons were responsive to kisspeptin stimulation, but hypothalamic expression of Kiss1 was reduced in the mutant mice. Our results showed that SIRT1 signaling in astrocytes can contribute to metabolic and reproductive regulation independent of SIRT1 effects in neurons.
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Ivanova, Margarita, Klaudia M. Dobrzycka, Shiming Jiang, Kai Michaelis, Rene Meyer, Kaiyan Kang, Brian Adkins, et al. "Scaffold Attachment Factor B1 Functions in Development, Growth, and Reproduction." Molecular and Cellular Biology 25, no. 8 (April 15, 2005): 2995–3006. http://dx.doi.org/10.1128/mcb.25.8.2995-3006.2005.
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ABSTRACT Scaffold attachment factor B1 (SAFB1) is a multifunctional protein that can bind both DNA and RNA and is involved in RNA processing and stress response. In addition, SAFB1 contains a transcriptional repression domain and can bind certain hormone receptors and repress their activity. To assess the role of SAFB1 in vivo, we generated SAFB1 mutant mice through targeted deletion in embryonic stem cells. While viable homozygous mutant (SAFB1−/−) mice were obtained, genotypic distribution indicated that homozygous deficiency resulted in both prenatal and neonatal lethality. Mice lacking SAFB1 exhibited dwarfism, as a result of in utero growth retardation, and had low serum insulin-like growth factor 1 (IGF1) levels. In agreement with the previous characterization of SAFB1 as a corepressor for hormone receptors, we found that SAFB1−/− mice displayed dramatic defects in the development and function of the reproductive system. Male SAFB1 null mice were infertile, apparently because of low circulating levels of testosterone. SAFB1−/− testes were small and showed progressive degeneration of the germinal epithelium, increased apoptosis of germ cells, and Leydig cell hyperplasia. SAFB−/− female mice were subfertile and showed progressive infertility, in part because of defects in oviductal transport and reduced numbers of follicles. Immortalized SAFB1−/− mouse embryonic fibroblasts showed cell-intrinsic defects including increased transcriptional estrogen receptor α activity and enhanced responsiveness to IGF1. Together, these in vivo findings establish a critical role for SAFB1 in development, growth regulation, and reproduction.
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Kim, Joshua, Sheila J. Semaan, Donald K. Clifton, Robert A. Steiner, Sangeeta Dhamija, and Alexander S. Kauffman. "Regulation of Kiss1 Expression by Sex Steroids in the Amygdala of the Rat and Mouse." Endocrinology 152, no. 5 (March 1, 2011): 2020–30. http://dx.doi.org/10.1210/en.2010-1498.
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Kisspeptin (encoded by the Kiss1 gene) is an important regulator of reproduction. In rodents, Kiss1 is expressed in two hypothalamic regions, the arcuate nucleus and anteroventral periventricular/ periventricular continuum, where it is regulated by sex steroids. However, the distribution, regulation, and functional significance of neural kisspeptin outside of the hypothalamus have not been studied and are poorly understood. Here, we report the expression of Kiss1 in the amygdala, predominantly in the medial nucleus of the amygdala (MeA), a region implicated in social and emotional behaviors as well as various aspects of reproduction. In gonadally intact rats and mice, Kiss1-expressing neurons were identified in the MeA of both sexes, with higher Kiss1 expression levels in adult males than females in diestrus. In rats, Kiss1 expression in the MeA changed as a function of the estrous cycle, with highest levels at proestrus. Next, we tested whether Kiss1 in the MeA is regulated by the circulating sex steroid milieu. Kiss1 levels in the MeA were low in gonadectomized mice and rats of both sexes, and treatment with either testosterone or estradiol amplified Kiss1 expression in this region. Testosterone's inductive effect on Kiss1 expression in the MeA likely occurs via estrogen receptor-dependent pathways, not through the androgen receptor, because dihydrotestosterone (a nonaromatizable androgen) did not affect MeA Kiss1 levels. Thus, in rodents, Kiss1 is expressed and regulated by sex steroids in the MeA of both sexes and may play a role in modulating reproduction or brain functions that extend beyond reproduction.
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O.I., Kit,, Frantsiyants, E.M., Neskubina, I.V., Kaplieva, I.V., Shikhlyarova, A.I., Trepitaki, L.K., Nemashkalova, L.A., and Pogorelova, Yu.A. "MITOCHONDRIAL DYSFUNCTION UNDER THE GROWTH OF B16/F10 MELANOMA IN C57BL/6 MICE." CARDIOMETRY, no. 24 (November 30, 2022): 21–23. http://dx.doi.org/10.18137/cardiometry.2022.24.conf.9.
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Mitochondria are present in all organs and tissues of the organism being responsible for the control of various aspects of the cellular function, providing the necessary supply of ATP, regulating Ca2+ signaling, controlling levels of reactive oxygen species (ROS) etc. Mitochondria perform specialized functions unique to certain tissues. Abnormalities in mitochondria disorder the key physiological functions such as the ATP production, oxidative phosphorylation, the reactive oxygen species production, and the Ca2+ regulation. This is considered as the mitochondrial dysfunction [5]. It is known that tumor mitochondria undergo some adaptive changes to further accelerate the rapid reproduction of tumor cells in an acidic and hypoxic microenvironment [2].
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Nothnick, Warren B. "The role of micro-RNAs in the female reproductive tract." REPRODUCTION 143, no. 5 (May 2012): 559–76. http://dx.doi.org/10.1530/rep-11-0240.
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Proper development and function of the female reproductive tract are essential for successful reproduction. Regulation of the differentiated functions of the organs that make up the female reproductive tract is well established to occur at multiple levels including transcription, translation, and posttranslational modifications. Micro-RNA (miRNA)-mediated posttranscriptional gene regulation has emerged as a fundamental mechanism controlling normal tissue development and function. Emerging evidence indicates that miRNAs are expressed within the organs of the female reproductive tract where they function to regulate cellular pathways necessary for proper function of these organs. In this review, the functional significance of miRNAs in the development and function of the organs of the female reproductive tract is discussed. Initial discussion focuses on the role of miRNAs in the development of the organs of the female reproductive tract highlighting recent studies that clearly demonstrate that mice with disrupted Dicer1 expression are sterile, fail to develop uterine glands, and have muted estrogen responsiveness. Next, emphasis moves to discussion on our current knowledge on the characterization of miRNA expression in each of the organs of the female reproductive tract. When possible, information is presented and discussed with respect to regulation, function, and/or functional targets of these miRNA within each specific organ of the female reproductive tract.
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Toufaily, Chirine, Gauthier Schang, Xiang Zhou, Philipp Wartenberg, Ulrich Boehm, John P. Lydon, Ferdinand Roelfsema, and Daniel J. Bernard. "Impaired LH surge amplitude in gonadotrope-specific progesterone receptor knockout mice." Journal of Endocrinology 244, no. 1 (January 2020): 111–22. http://dx.doi.org/10.1530/joe-19-0013.
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The progesterone receptor (PR, encoded by Pgr) plays essential roles in reproduction. Female mice lacking the PR are infertile, due to the loss of the protein’s functions in the brain, ovary, and uterus. PR is also expressed in pituitary gonadotrope cells, but its specific role therein has not been assessed in vivo. We therefore generated gonadotrope-specific Pgr conditional knockout mice (cKO) using the Cre-LoxP system. Overall, both female and male cKO mice appeared phenotypically normal. cKO females displayed regular estrous cycles (vaginal cytology) and normal fertility (litter size and frequency). Reproductive organ weights were comparable between wild-type and cKO mice of both sexes, as were production and secretion of the gonadotropins, LH and FSH, with one exception. On the afternoon of proestrus, the amplitude of the LH surge was blunted in cKO females relative to controls. Contrary to predictions of earlier models, this did not appear to derive from impaired GnRH self-priming. Collectively, these data indicate that PR function in gonadotropes may be limited to regulation of LH surge amplitude in female mice via a currently unknown mechanism.
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Mujoomdar, Michelle L., Laura M. Hogan, Albert F. Parlow, and Mark W. Nachtigal. "Pcsk6 mutant mice exhibit progressive loss of ovarian function, altered gene expression, and formation of ovarian pathology." REPRODUCTION 141, no. 3 (March 2011): 343–55. http://dx.doi.org/10.1530/rep-10-0451.
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Bioactivation of precursor proteins by members of the proprotein convertase (PC) family is essential for normal reproduction. ThePcsk6gene is a member of the PC family that is expressed in numerous ovarian cell types including granulosa cells and oocytes. We hypothesized that loss of PCSK6 would produce adverse effects in the mouse ovary. Mice incapable of expressing PCSK6 (Pcsk6tm1Rob) were obtained, and reproductive parameters (serum hormones, whelping interval, estrus cyclicity, and fertility) were compared toPcsk6+/+mice. WhilePcsk6tm1Robfemale mice are fertile, they manifest reduced reproductive capacity at an accelerated rate relative toPcsk6+/+mice. Reproductive senescence is typically reached by 9 months of age and is correlated with loss of estrus cyclicity, elevated serum FSH levels, and gross alterations in ovarian morphology. A wide range of ovarian morphologies were identified encompassing mild, such as an apparent reduction in follicle number, to moderate – ovarian atrophy with a complete absence of follicles – to severe, manifesting as normal ovarian structures replaced by benign ovarian tumors, including tubulostromal adenomas. Targeted gene expression profiling highlighted changes in RNA expression of molecules involved in processes such as steroidogenesis, gonadotropin signaling, transcriptional regulation, autocrine/paracrine signaling, cholesterol handling, and proprotein bioactivation. These results show that PCSK6 activity plays a role in maintaining normal cellular and tissue homeostasis in the ovary.
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Burton, Kimberly A., and G. Stanley McKnight. "PKA, Germ Cells, and Fertility." Physiology 22, no. 1 (February 2007): 40–46. http://dx.doi.org/10.1152/physiol.00034.2006.
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Temporal and spatial regulation of PKA activity are essential for vigorous sperm motility and for the resumption of meiosis in oocytes, two events required for successful fertilization. Genetic mutations in mice that affect PKA signaling in germ cells lead to infertility and illustrate the importance of this pathway in mammalian reproduction.
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Mulac-Jericevic, Biserka, and Orla M. Conneely. "Reproductive tissue selective actions of progesterone receptors." Reproduction 128, no. 2 (August 2004): 139–46. http://dx.doi.org/10.1530/rep.1.00189.
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The steroid hormone, progesterone, plays a central coordinate role in diverse events associated with female reproduction. In humans and other vertebrates, the biological activity of progesterone is mediated by modulation of the transcriptional activity of two progesterone receptors, PR-A and PR-B. These receptors arise from the same gene and exhibit both overlapping and distinct transcriptional activitiesin vitro. To delineate the individual roles of PR-A and PR-Bin vivo, we have generated mouse models in which expression of a single PR isoform has been ablated. Analysis of the reproductive phenotypes of these mice has indicated that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive responses to progesterone. While selective ablation of the PR-A protein (PR-A knockout mice, PRAKO mice) shows normal mammary gland response to progesterone but severe uterine hyperplasia and ovarian abnormalities, ablation of PR-B protein (PRBKO mice) does not affect biological responses of the ovary or uterus to progesterone but results in reduced pregnancy-associated mammary gland morphogenesis. The distinct tissue-specific reproductive responses to progesterone exhibited by these isoforms are due to regulation of distinct subsets of progesterone-dependent target genes by the individual PR isoforms. This review will summarize our current understanding of the selective contribution of PR isoforms to the cellular and molecular actions of progesterone in reproductive tissues.
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Wang, Hong-Hui, Qian Cui, Teng Zhang, Lei Guo, Ming-Zhe Dong, Yi Hou, Zhen-Bo Wang, Wei Shen, Jun-Yu Ma, and Qing-Yuan Sun. "Removal of mouse ovary fat pad affects sex hormones, folliculogenesis and fertility." Journal of Endocrinology 232, no. 2 (February 2017): 155–64. http://dx.doi.org/10.1530/joe-16-0174.
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As a fat storage organ, adipose tissue is distributed widely all over the body and is important for energy supply, body temperature maintenance, organ protection, immune regulation and so on. In humans, both underweight and overweight women find it hard to become pregnant, which suggests that appropriate fat storage can guarantee the female reproductive capacity. In fact, a large mass of adipose tissue distributes around the reproductive system both in the male and female. However, the functions of ovary fat pad (the nearest adipose tissue to ovary) are not known. In our study, we found that the ovary fat pad-removed female mice showed decreased fertility and less ovulated mature eggs. We further identified that only a small proportion of follicles developed to antral follicle, and many follicles were blocked at the secondary follicle stage. The overall secretion levels of estrogen and FSH were lower in the whole estrus cycle (especially at proestrus); however, the LH level was higher in ovary fat pad-removed mice than that in control groups. Moreover, the estrus cycle of ovary fat pad-removed mice showed significant disorder. Besides, the expression of FSH receptor decreased, but the LH receptor increased in ovary fat pad-removed mice. These results suggest that ovary fat pad is important for mouse reproduction.
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Molnár, C. S., I. Kalló, Z. Liposits, and E. Hrabovszky. "Estradiol Down-Regulates RF-Amide-Related Peptide (RFRP) Expression in the Mouse Hypothalamus." Endocrinology 152, no. 4 (February 15, 2011): 1684–90. http://dx.doi.org/10.1210/en.2010-1418.
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Abstract In most mammals, RF-amide-related peptides are synthesized in the dorsomedial hypothalamic nucleus and regulate reproduction via inhibiting GnRH neurons and, possibly, adenohypophyseal gonadotrophs. In the present study, we investigated the possibility that RFRP-synthesizing neurons are involved in estrogen feedback signaling to the reproductive axis in mice. First, we used quantitative in situ hybridization and compared the expression of prepro-RFRP mRNA of ovariectomized mice, with and without 17β-estradiol (E2) replacement. Subcutaneous administration of E2 via silastic capsules for 4 d significantly down-regulated prepro-RFRP mRNA expression. The underlying receptor mechanism was investigated with immunohistochemistry. In ovariectomized mice, low levels of nuclear estrogen receptor (ER)-α immunoreactivity were detectable in 18.7 ± 3.8% of RFRP neurons. The majority of RFRP neurons showed no ER-α signal, and RFRP neurons did not exhibit ER-β immunoreactivity. Results of these studies indicate that RFRP is a negatively estradiol-regulated neurotransmitter/neuromodulator in mice. The estrogenic down-regulation of RFRP expression may contribute to estrogen feedback to the reproductive axis. The issue of whether E2 regulates RFRP neurons directly or indirectly remains open given that ER-α immunoreactivity is present only at low levels in a subset of these cells.
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Shao, Ruijin, Magdalena Nutu, Linda Karlsson-Lindahl, Anna Benrick, Birgitta Weijdegård, Susanne Lager, Emil Egecioglu, et al. "Downregulation of cilia-localized Il-6Rα by 17β-estradiol in mouse and human fallopian tubes." American Journal of Physiology-Cell Physiology 297, no. 1 (July 2009): C140—C151. http://dx.doi.org/10.1152/ajpcell.00047.2009.
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The action of interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6Rα and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6Rα is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17β-estradiol (E2), but not progesterone (P4), causes a time-dependent decrease in IL-6Rα expression, which is blocked by the estrogen receptor (ER) antagonist ICI-182,780. Exposure of different ER-selective agonists propyl-(1H)-pyrazole-1,3,5-triyl-trisphenol or 2,3-bis-(4-hydroxyphenyl)-propionitrile demonstrated an ER subtype-specific regulation of IL-6Rα in mouse fallopian tubes. In contrast to IL-6Rα, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6Rα and gp130 in IL-6 knockout mice was found to be normal; however, E2 treatment increased IL-6Rα, but not gp130, in IL-6 knockout mice when compared with wild-type mice. Furthermore, expression levels of IL-6Rα, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings open the posibility that cilia-specific IL-6Rα may play a role in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6Rα in the fallopian tube.
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Blum, Thomas, Ana Moreno-Pérez, Martina Pyrski, Bernd Bufe, Anela Arifovic, Petra Weissgerber, Marc Freichel, Frank Zufall, and Trese Leinders-Zufall. "Trpc5 deficiency causes hypoprolactinemia and altered function of oscillatory dopamine neurons in the arcuate nucleus." Proceedings of the National Academy of Sciences 116, no. 30 (July 8, 2019): 15236–43. http://dx.doi.org/10.1073/pnas.1905705116.
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Dopamine neurons of the hypothalamic arcuate nucleus (ARC) tonically inhibit the release of the protein hormone prolactin from lactotropic cells in the anterior pituitary gland and thus play a central role in prolactin homeostasis of the body. Prolactin, in turn, orchestrates numerous important biological functions such as maternal behavior, reproduction, and sexual arousal. Here, we identify the canonical transient receptor potential channel Trpc5 as an essential requirement for normal function of dopamine ARC neurons and prolactin homeostasis. By analyzing female mice carrying targeted mutations in the Trpc5 gene including a conditional Trpc5 deletion, we show that Trpc5 is required for maintaining highly stereotyped infraslow membrane potential oscillations of dopamine ARC neurons. Trpc5 is also required for eliciting prolactin-evoked tonic plateau potentials in these neurons that are part of a regulatory feedback circuit. Trpc5 mutant females show severe prolactin deficiency or hypoprolactinemia that is associated with irregular reproductive cyclicity, gonadotropin imbalance, and impaired reproductive capabilities. These results reveal a previously unknown role for the cation channel Trpc5 in prolactin homeostasis of female mice and provide strategies to explore the genetic basis of reproductive disorders and other malfunctions associated with defective prolactin regulation in humans.
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Kauffman, Alexander S., Víctor M. Navarro, Joshua Kim, Donald K. Clifton, and Robert A. Steiner. "Sex differences in the regulation of Kiss1/NKB neurons in juvenile mice: implications for the timing of puberty." American Journal of Physiology-Endocrinology and Metabolism 297, no. 5 (November 2009): E1212—E1221. http://dx.doi.org/10.1152/ajpendo.00461.2009.
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In mammals, puberty onset typically occurs earlier in females than in males, but the explanation for sexual differentiation in the tempo of pubertal development is unknown. Puberty in both sexes is a brain-dependent phenomenon and involves alterations in the sensitivity of neuronal circuits to gonadal steroid feedback as well as gonadal hormone-independent changes in neuronal circuitry. Kisspeptin, encoded by the Kiss1 gene, plays an essential but ill-defined role in pubertal maturation. Neurokinin B (NKB) is coexpressed with Kiss1 in the arcuate nucleus (ARC) and is also important for puberty. We tested whether sex differences in the timing of pubertal development are attributable to sexual differentiation of gonadal hormone-independent mechanisms regulating hypothalamic Kiss1/NKB gene expression. We found that, in juvenile females, gonadotropin secretion and expression of Kiss1 and NKB in the ARC increased immediately following ovariectomy, suggesting that prepubertal females have negligible gonadal hormone-independent restraint on their reproductive axis. In contrast, in similarly aged juvenile males, no changes occurred in LH levels or Kiss1 or NKB expression following castration, suggesting that gonadal hormone-independent mechanisms restrain kisspeptin/NKB-dependent activation of the male reproductive axis before puberty. Notably, adult mice of both sexes showed comparable rapid increases in Kiss1/NKB expression and LH secretion following gonadectomy, signifying that sex differences in the regulation of ARC Kiss1/NKB neurons are manifest only during peripubertal development. Our findings demonstrate that the mechanisms controlling pubertal activation of reproduction in mice are different between the sexes and suggest that gonadal hormone-independent central restraint on pubertal timing involves Kiss1/NKB neurons in the ARC.
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Israel, Davelene D., Sharone Sheffer-Babila, Carl de Luca, Young-Hwan Jo, Shun Mei Liu, Qiu Xia, Daniel J. Spergel, Siok L. Dun, Nae J. Dun, and Streamson C. Chua. "Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction." Endocrinology 153, no. 5 (March 9, 2012): 2408–19. http://dx.doi.org/10.1210/en.2011-1822.
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Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agouti-related peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.
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Yang, Chan, Zaohong Ran, Guoshi Liu, Rong Hou, Changjiu He, Qinghua Liu, Yingjun Chen, et al. "Melatonin Administration Accelerates Puberty Onset in Mice by Promoting FSH Synthesis." Molecules 26, no. 5 (March 9, 2021): 1474. http://dx.doi.org/10.3390/molecules26051474.
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Although melatonin has been extensively studied in animal reproduction, the mechanism of melatonin in puberty remains elusive. This study was designed to explore the effect of intraperitoneal administration of melatonin on puberty onset in female mice. The injection of melatonin into postnatal days 10 mice at a dose of 15 mg/kg accelerated the puberty onset in mice. Mechanistically, there was no difference in physical growth and serum Leptin levels after melatonin administration. Meanwhile, the serum levels of reproductive hormones involved in hypothalamic-pituitary-ovarian axis, such as FSH and estrogen level in serum were increased. The mRNA levels of GnRH and GnRHr were not affected by melatonin, while the expressions of FSHβ in pituitary and Cyp19a1 in ovary were significantly up-regulated. In addition, melatonin still promoted FSH synthesis after ovariectomy. Furthermore, the enhanced activity of ERK1/2 signaling verified that the expression of FSHβ increased in pituitary. We confirmed that melatonin promoted the FSH synthesis in pituitary, thereby increased serum estrogen levels and ultimately accelerated puberty onset. However, these effects of melatonin may be pharmacological due to the high dose. This study would help us to understand the functions of melatonin in pubertal regulation comprehensively.
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Scott, M. E. "An experimental and theoretical study of the dynamics of a mouse – nematode (Heligmosomoides polygyrus) interaction." Parasitology 101, no. 1 (August 1990): 75–92. http://dx.doi.org/10.1017/s0031182000079786.
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SUMMARYThe population dynamics of outbred laboratory mice in indoor enclosures in the absence and presence of a naturally transmitted direct life-cycle nematode Heligmosomoides polygyrus Dujardin 1845 were reported previously. This manuscript presents further information on the age and sex structure of the populations, results of experiments designed to estimate the density-dependent effect of the parasite on host survival and reproduction, and a mathematical model of both uninfected and infected mouse populations. In the uninfected mouse population, survival of female mice was age- and density-independent, survival of male mice was age-dependent and density-independent, and recruitment was density-dependent. Independent experiments revealed that the parasite had no density-dependent effect on mouse reproduction, but had density-dependent effects on both acute and chronic survival of mice. An age-structured Leslie matrix model captured the exponential growth and plateau of the uninfected mouse population. Modification of the model to incorporate the effects of the parasite provided a good fit to the data from the infected populations, supporting the hypothesis that density-dependent effects of the parasite on host survival could lead to regulation of host abundance.
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Navarro, Víctor M., Martha A. Bosch, Silvia León, Serap Simavli, Cadence True, Leonor Pinilla, Rona S. Carroll, et al. "The Integrated Hypothalamic Tachykinin-Kisspeptin System as a Central Coordinator for Reproduction." Endocrinology 156, no. 2 (November 25, 2014): 627–37. http://dx.doi.org/10.1210/en.2014-1651.
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Tachykinins are comprised of the family of related peptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB). NKB has emerged as regulator of kisspeptin release in the arcuate nucleus (ARC), whereas the roles of SP and NKA in reproduction remain unknown. This work explores the roles of SP and NKA in the central regulation of GnRH release. First, central infusion of specific agonists for the receptors of SP (neurokinin receptor 1, NK1R), NKA (NK2R) and NKB (NK3R) each induced gonadotropin release in adult male and ovariectomized, estradiol-replaced female mice, which was absent in Kiss1r−/− mice, indicating a kisspeptin-dependent action. The NK2R agonist, however, decreased LH release in ovariectomized-sham replaced females, as documented for NK3R agonists but in contrast to the NK1R agonist, which further increased LH release. Second, Tac1 (encoding SP and NKA) expression in the ARC and ventromedial nucleus was inhibited by circulating estradiol but did not colocalize with Kiss1 mRNA. Third, about half of isolated ARC Kiss1 neurons expressed Tacr1 (NK1R) and 100% Tacr3 (NK3R); for anteroventral-periventricular Kiss1 neurons and GnRH neurons, approximately one-fourth expressed Tacr1 and one-tenth Tacr3; Tacr2 (NK2R) expression was absent in all cases. Overall, these results identify a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems in the presence of kisspeptin-Kiss1r signaling, indicating that they may, along with NKB/NK3R, control GnRH release, at least in part through actions on Kiss1 neurons.
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Walther, T., and H. Stepan. "C-type natriuretic peptide in reproduction, pregnancy and fetal development." Journal of Endocrinology 180, no. 1 (January 1, 2004): 17–22. http://dx.doi.org/10.1677/joe.0.1800017.
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C-type natriuretic peptide (CNP) belongs to the natriuretic peptide family that consists of three structurally related peptides with a 17-amino acid ring linked by a disulfide bond. In contrast to atrial and brain natriuretic peptides that are mainly cardiovascular hormones, CNP acts predominantly in an autocrine/paracrine fashion, is commonly considered to be an endothelial hormone with antimitogenic properties, and is characterized as a regulator of endochondral ossification. Its biological effects are mediated by an intracellular cGMP accumulation via specific membrane-bound guanylyl cyclase B (GC-B) activation. There is growing evidence that this peptide is also involved in various reproductive processes as well as in embryonic and fetal development. In rodents, CNP and its receptor are highly expressed in the uterus and ovaries with specific regulation during the estrous cycle. During pregnancy, CNP mRNA is detectable in mice embryos and shows an organ-specific expression in maternal reproductive tIssues with the highest concentration in the placenta. This could indicate a defined biological function of the CNP/GC-B/cGMP axis in gestation e.g. antagonizing vasoconstrictive peptides like angiotensin II. In humans, besides a postulated fetal de novo synthesis of CNP, both the peptide and its receptor are expressed in the placenta and myometrium with opposite regulation of CNP in pregnancies complicated by pre-eclampsia or intrauterine growth retardation. Since the maternal plasma levels do not reflect these alterations, one can conclude that this part of the natriuretic peptide system acts locally suggesting that CNP-stimulated cGMP release exhibits organ-specific effects. Importantly, CNP has also become a peptide with a distinct role in male reproductive processes, since endocrine function of the testis and the regulation of penile erection are regulated by the CNP/GC-B axis. This review gives a comprehensive overview of the multiple functions of CNP in reproduction and pregnancy as well as in embryonic and fetal development.
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Kondo, Yasuhiko, and Himeka Hayashi. "Neural and Hormonal Basis of Opposite-Sex Preference by Chemosensory Signals." International Journal of Molecular Sciences 22, no. 15 (August 2, 2021): 8311. http://dx.doi.org/10.3390/ijms22158311.
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In mammalian reproduction, sexually active males seek female conspecifics, while estrous females try to approach males. This sex-specific response tendency is called sexual preference. In small rodents, sexual preference cues are mainly chemosensory signals, including pheromones. In this article, we review the physiological mechanisms involved in sexual preference for opposite-sex chemosensory signals in well-studied laboratory rodents, mice, rats, and hamsters of both sexes, especially an overview of peripheral sensory receptors, and hormonal and central regulation. In the hormonal regulation section, we discuss potential rodent brain bisexuality, as it includes neural substrates controlling both masculine and feminine sexual preferences, i.e., masculine preference for female odors and the opposite. In the central regulation section, we show the substantial circuit regulating sexual preference and also the influence of sexual experience that innate attractants activate in the brain reward system to establish the learned attractant. Finally, we review the regulation of sexual preference by neuropeptides, oxytocin, vasopressin, and kisspeptin. Through this review, we clarified the contradictions and deficiencies in our current knowledge on the neuroendocrine regulation of sexual preference and sought to present problems requiring further study.
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Christensen, Heather R., Michael K. Murawsky, Nelson D. Horseman, Tara A. Willson, and Karen A. Gregerson. "Completely Humanizing Prolactin Rescues Infertility in Prolactin Knockout Mice and Leads to Human Prolactin Expression in Extrapituitary Mouse Tissues." Endocrinology 154, no. 12 (December 1, 2013): 4777–89. http://dx.doi.org/10.1210/en.2013-1476.
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A variety of fundamental differences have evolved in the physiology of the human and rodent prolactin (PRL) systems. The PRL gene in humans and other primates contains an alternative promoter, 5.8 kbp upstream of the pituitary transcription start site, which drives expression of PRL in “extrapituitary” tissues, where PRL is believed to exert local, or paracrine, actions. Several of these extrapituitary PRL tissues serve a reproductive function (eg, mammary gland, decidua, prostate, etc), consistent with the hypothesis that local PRL production may be involved in, and required for, normal reproductive physiology in primates. Rodent research models have generated significant findings regarding the role of PRL in reproduction. Specifically, disruption (knockout) of either the PRL gene or its receptor causes profound female reproductive defects at several levels (ovaries, preimplantation endometrium, mammary glands). However, the rodent PRL gene differs significantly from the human, most notably lacking the alternative promoter. Understanding of the physiological regulation and function of extrapituitary PRL has been limited by the absence of a readily accessible experimental model, because the rodent PRL gene does not contain the alternative promoter. To overcome these limitations, we have generated mice that have been “humanized” with regard to the structural gene and tissue expression of PRL. Here, we present the characterization of these animals, demonstrating that the human PRL transgene is responsive to known physiological regulators both in vitro and in vivo. More importantly, the expression of the human PRL transgene is able to rescue the reproductive defects observed in mouse PRL knockout (mPRL−) females, validating their usefulness in studying the function or regulation of this hormone in a manner that is relevant to human physiology.
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Macedo, Delanie B., Ana Paula Abreu, Melissa Magnuson, Han Kyeol Kim, Alessandra Mancini, Ana Claudia Latronico, Rona Stephanie Carroll, and Ursula B. Kaiser. "Pubertal Onset Occurs in Female Mice Lacking Paternally Expressed Dlk1 Despite Lower Leptin and Kisspeptin Levels." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A688. http://dx.doi.org/10.1210/jendso/bvab048.1401.
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Abstract The timing of puberty in females is highly sensitive to metabolic cues and energy reserves. Epidemiologic studies indicate a relationship between increased body mass index and earlier puberty in girls. In contrast, a significant delay in puberty and menarche is seen in girls who have diminished body fat. Multiple peripheral hormones are responsible for transmitting metabolic information to hypothalamic kisspeptin and GnRH neurons. Sufficient levels of leptin, an adipose tissue hormone with a permissive/stimulatory effect on the metabolic control of reproduction, are required for puberty onset, reproductive function and fertility. Loss-of-function mutations in the Delta-like homolog 1 (DLK1) gene have been described in girls with central precocious puberty (CPP) and increased body fat, suggesting a link between metabolism and reproduction. DLK1 is a paternally expressed gene located on human chromosome 14q32.2 in a locus associated with Temple syndrome (TS). Dlk1 knockout mice display pre- and postnatal growth retardation, a phenotype that overlaps with TS. We have shown that Dlk1 deficient female mice achieved puberty at the same age as wild type mice, despite a considerably lower body weight (BW) (“relative precocious puberty”). To date, the mechanisms of action of Dlk1 in determining pubertal onset remain unknown. In this study, we used a Dlk1 deficient mouse model to explore the influence of Dlk1 in the regulation of reproductive axis, particularly its effects on leptin and/or kisspeptin, a major excitatory factor of the reproductive axis. By RT-qPCR and Western blot, we confirmed that both Dlk1 mRNA and protein were undetectable in the mediobasal hypothalamus (MBH) of Dlk+/p- (which inherited the mutant allele from their father), but it was present in Dlk+/+ mice. White adipose tissue (WAT) and blood were collected from Dlk+/p- and Dlk+/+ female mice at postnatal day (PND) 26, and MBH tissue was obtained from both groups at PND 15, 26 and 60. Quantification of total WAT showed no significant difference between Dlk1+/p-and Dlk1+/+ mice (p=0.8) at PND26, even after correction for total BW (p=0.29). Hypothalamic mRNA levels of Kiss1 and Socs3, a downstream mediator of leptin signaling, were measured by RT-qPCR. Kiss1 mRNA levels were significantly reduced in the MBH of Dlk1+/p- mice at PND15 and PND60, but no significant difference was found at PND 26. Socs3 expression was significantly lower in Dlk1+/p- mice (p=0.04) as a result of the reduced circulating levels of leptin (ELISA) observed in these mice at PDN26 (p=0.01). Our findings suggest that the absence of Dlk1 may attenuate the metabolic effects of low body weight and low leptin levels on puberty onset and that, as seen in humans, DLK1 is an important link between body weight and pubertal development. Finally, Dlk1 deficiency leads to activation of the reproductive axis despite lower levels of kisspeptin.
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Krasnow, Stephanie M., Gregory S. Fraley, Sonya M. Schuh, James W. Baumgartner, Donald K. Clifton, and Robert A. Steiner. "A Role for Galanin-Like Peptide in the Integration of Feeding, Body Weight Regulation, and Reproduction in the Mouse." Endocrinology 144, no. 3 (March 1, 2003): 813–22. http://dx.doi.org/10.1210/en.2002-220982.
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Galanin-like peptide (GALP) shares sequence homology with galanin and binds to galanin receptors in vitro. GALP neurons in the arcuate nucleus coexpress leptin receptors, and GALP mRNA expression is up-regulated by leptin. Based on these observations, we postulated that GALP plays a role in mediating leptin’s inhibitory effects on food intake (FI) and body weight (BW), as well as its stimulatory effect on the reproductive axis. To test these hypotheses, we performed several studies in which mice received intracerebroventricular injections of either GALP or vehicle. Acute GALP treatment elicited a dose-dependent suppression of FI and BW. Long-term treatment with GALP caused only transient reductions in FI and BW, demonstrating that the mice became refractory to continued exposure to GALP. GALP inhibited FI as early as 1 h post injection. Central injection of GALP suppressed locomotor activity and elicited the formation of a conditioned taste aversion. In male mice, serum levels of LH and testosterone were increased by GALP administration. Although we cannot rule out possible nonspecific effects of GALP on FI, the present observations are consistent with the argument that GALP is a downstream effector of leptin’s actions within the central nervous system.
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Gottsch, Michelle L., Hongkui Zeng, John G. Hohmann, David Weinshenker, Donald K. Clifton, and Robert A. Steiner. "Phenotypic Analysis of Mice Deficient in the Type 2 Galanin Receptor (GALR2)." Molecular and Cellular Biology 25, no. 11 (June 1, 2005): 4804–11. http://dx.doi.org/10.1128/mcb.25.11.4804-4811.2005.
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ABSTRACT Galanin is a neuropeptide implicated in the regulation of feeding, reproduction, cognition, nociception, and seizure susceptibility. There are three known galanin receptor (GALR) subtypes (GALR1, GALR2, and GALR3), which bind to galanin with different affinities and have their own unique distributions, signaling mechanisms, and putative functions in the brain and peripheral nervous system. To gain further insight into the possible physiological significance of GALR2, we created mutant mice that were deficient in GALR2 and compared their phenotype to that of wild-type (WT) littermate or age-matched controls, with respect to basic motor and sensory function, feeding behavior, reproduction, mood, learning and memory, and seizure susceptibility. Phenotypic analysis revealed that animals bearing a deletion of GALR2 did not differ significantly from their WT controls in any of the measured variables. We conclude that either GALR2 plays no role in these physiological functions or through redundancy or compensation these mutant animals can adapt to the congenital absence of GALR2. It is also conceivable that GALR2 plays only a subtle role in some of these functions and that the impact of its loss could not be detected by the analytical procedures used here.
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Dupuis, Lisa, Yasmin Schuermann, Tamara Cohen, Dayananda Siddappa, Anitha Kalaiselvanraja, Melissa Pansera, Vilceu Bordignon, and Raj Duggavathi. "Role of leptin receptors in granulosa cells during ovulation." REPRODUCTION 147, no. 2 (February 2014): 221–29. http://dx.doi.org/10.1530/rep-13-0356.
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Leptin is an important hormone influencing reproductive function. However, the mechanisms underpinning the role of leptin in the regulation of reproduction remain to be completely deciphered. In this study, our objective is to understand the mechanisms regulating the expression of leptin receptor (Lepr) and its role in ovarian granulosa cells during ovulation. First, granulosa cells were collected from superovulated mice to profile mRNA expression of Lepr isoforms (LeprA and LeprB) throughout follicular development. Expression of LeprA and LeprB was dramatically induced in the granulosa cells of ovulating follicles at 4 h after human chorionic gonadotropin (hCG) treatment. Relative abundance of both mRNA and protein of CCAAT/enhancer-binding protein β (Cebpβ) increased in granulosa cells from 1 to 7 h post-hCG. Furthermore, chromatin immunoprecipitation assay confirmed the recruitment of Cebpβ to Lepr promoter. Thus, hCG-induced transcription of Lepr appears to be regulated by Cebpβ, which led us to hypothesise that Lepr may play a role during ovulation. To test this hypothesis, we used a recently developed pegylated superactive mouse leptin antagonist (PEG-SMLA) to inhibit Lepr signalling during ovulation. I.p. administration of PEG-SMLA (10 μg/g) to superovulated mice reduced ovulation rate by 65% compared with control treatment. Although the maturation stage of the ovulated oocytes remained unaltered, ovulation genes Ptgs2 and Has2 were downregulated in PEG-SMLA-treated mice compared with control mice. These results demonstrate that Lepr is dramatically induced in the granulosa cells of ovulating follicles and this induction of Lepr expression requires the transcription factor Cebpβ. Lepr plays a critical role in the process of ovulation by regulating, at least in part, the expression of the important genes involved in the preovulatory maturation of follicles.
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Ge, Xiyu, Karen Weis, and Lori Raetzman. "Prenatal Exposure to the Endocrine Disrupting Chemical DEHP Impacts Reproduction-Related Gene Expression in the Pituitary." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A491. http://dx.doi.org/10.1210/jendso/bvab048.1004.
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Abstract Phthalates are chemicals used in various common products including plastics and medical devices, leading to widespread contact. Phthalate exposure during embryonic development can cause changes in puberty timing, reduced fertility and genital abnormalities. Previous studies on prenatal exposure to Di-(2-ethylhexyl) phthalate (DEHP) in mice indicated that it disrupts pituitary-gonadal feedback and alters reproductive performance in the offspring, however, the mechanism behind this is unknown. We hypothesize that prenatal exposure to DEHP during a critical period of embryonic development (e15.5 to e18.5) will cause sex-specific disruptions in reproduction-related functions in the pituitary in offspring due to interference with androgen and aryl hydrocarbon receptor (AhR) signaling. In order to discover the direct effects of DEHP on the reproduction-related functions in the pituitary, we performed both in vivo dosing and in vitro pituitary culture experiments. First, we dosed pregnant CD-1 mice with corn oil, the antiandrogen flutamide or DEHP from gestational day 15.5 to 18.5, then collected the pituitaries of the offspring on postnatal day 0. We found that prenatal DEHP exposure caused a significant increase in Fshb specifically in males, and flutamide caused significant increases in both Lhb and Fshb in males. Besides, DEHP exposure significantly increased AhR pathway related gene Cyp1b1 in both males and females. In the in vitro experiment, we took whole pituitaries from e16.5 embryos and cultured them in media containing DEHP, MEHP and/or AhR antagonist for 72hrs. We found that the DEHP metabolite MEHP was actually the chemical that exerted the effects directly at the level of the pituitary. Similar to in vivo experiments, Cyp1a1 and Cyp1b1 mRNA level were increased in pituitaries treated with MEHP in both sexes and the induction could be reduced by co-treatment with AhR antagonist. The mRNA level of Lhb, Fshb and Gnrhr were significantly decreased in both sexes by MEHP and co-treatment with AhR antagonist did not restore mRNA levels. The induction of Cyp1a1/Cyp1b1 gene in both in vivo and in vitro experiments indicates the possible activation of AhR by DEHP/MEHP. The in vitro experiment with AhR antagonist further proved that the induction of Cyp1a1/Cyp1b1 was indeed due to AhR activation directly at the level of the pituitary. The difference between in vivo and in vitro experiments in terms of gonadotropin gene expression indicates multiple mechanisms should be involved in the regulation of gonadotropin gene expression in vivo including androgen-related pathways and possibly AhR-related pathways. In summary, our data suggest that phthalates can directly affect the function of the pituitary in terms of regulation of reproductive- related genes. This indicates that pituitary impacts of phthalates could contribute to reproductive dysfunction observed in exposed mice and humans.
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Sengupta, Pallav. "AN UPDATE ON COAGULATING GLAND RENIN-ANGIOTENSIN-PROSTAGLANDIN SYSTEM: A NEW HYPOTHESIS ON ITS RENIN FUNCTION." Asian Journal of Pharmaceutical and Clinical Research 10, no. 5 (May 1, 2017): 47. http://dx.doi.org/10.22159/ajpcr.2017.v10i5.17427.
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After proper description of reproductive functions of rodent anterior prostate, coagulating gland (CG), by Moore and Gallagher in 1930, numerous papers have been published on this gland and its function in male fertility. It has also been known that it has a local renin-angiotensin system (RAS). But, the actual function of this system is not very clear, and even now-a-days, this gland is getting ignored in reproductive physiology research. Thus, this review article attempts to unearth the reproductive functions of this gland, with a hypothetical mechanism of CG renin function. We have reviewed the available literature published on this gland and correlated the fragmented information to unveil its importance. We have proposed a hypothetical mechanism (aided by self-designed schemes) of CG renin function along with its functional and structural aspects in reproductive physiology. Despite being ignored in modern research, CG has a very significant function in rodent reproduction and breeding. It has also a very significant role in regulation of local homeostasis by renin-angiotensin-prostaglandin system.Key words:laboratory rat; mice; accessory sex organs; coagulating gland; renin
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Gimpl, Gerald, and Falk Fahrenholz. "The Oxytocin Receptor System: Structure, Function, and Regulation." Physiological Reviews 81, no. 2 (April 1, 2001): 629–83. http://dx.doi.org/10.1152/physrev.2001.81.2.629.
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The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF2α. Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF2α. Thus, to initiate labor, it might be essential to generate sufficient PGF2α to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.
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Whirledge, Shannon D., Robert H. Oakley, Page H. Myers, John P. Lydon, Francesco DeMayo, and John A. Cidlowski. "Uterine glucocorticoid receptors are critical for fertility in mice through control of embryo implantation and decidualization." Proceedings of the National Academy of Sciences 112, no. 49 (November 23, 2015): 15166–71. http://dx.doi.org/10.1073/pnas.1508056112.
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In addition to the well-characterized role of the sex steroid receptors in fertility and reproduction, organs of the female reproductive tract are also regulated by the hypothalamic–pituitary–adrenal axis. These endocrine organs are sensitive to stress-mediated actions of glucocorticoids, and the mouse uterus contains high levels of the glucocorticoid receptor (GR). Although the presence of GR in the uterus is well established, uterine glucocorticoid signaling has been largely ignored in terms of its reproductive and/or immunomodulatory functions on fertility. To define the direct in vivo function of glucocorticoid signaling in adult uterine physiology, we generated a uterine-specific GR knockout (uterine GR KO) mouse using the PRcre mouse model. The uterine GR KO mice display a profound subfertile phenotype, including a significant delay to first litter and decreased pups per litter. Early defects in pregnancy are evident as reduced blastocyst implantation and subsequent defects in stromal cell decidualization, including decreased proliferation, aberrant apoptosis, and altered gene expression. The deficiency in uterine GR signaling resulted in an exaggerated inflammatory response to induced decidualization, including altered immune cell recruitment. These results demonstrate that GR is required to establish the necessary cellular context for maintaining normal uterine biology and fertility through the regulation of uterine-specific actions.
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Groussin, L., and J. Bertherat. "Transcriptional regulation by cyclic AMP is essential for development, reproduction and survival: lessons from the transgenic mice." European Journal of Endocrinology 139, no. 6 (December 1, 1998): 571–72. http://dx.doi.org/10.1530/eje.0.1390571.
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Guerra, Damian D., Rachael Bok, Evelyn Llerena Cari, Cari Nicholas, David J. Orlicky, Joshua Johnson, and K. Joseph Hurt. "Effect of neuronal nitric oxide synthase serine-1412 phosphorylation on hypothalamic–pituitary–ovarian function and leptin response." Biology of Reproduction 102, no. 6 (February 26, 2020): 1281–89. http://dx.doi.org/10.1093/biolre/ioaa025.
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Abstract Hypothalamic neuronal nitric oxide synthase (nNOS) potentiates adult female fertility in rodents by stimulating gonadotropin releasing hormone (GnRH) secretion, which in turn promotes luteinizing hormone (LH) release and ovulation. The mechanism of hypothalamic nNOS activation is not clear but could be via nNOS serine1412 (S1412) phosphorylation, which increases nNOS activity and physiologic NO effects in other organ systems. In female rodents, hypothalamic nNOS S1412 phosphorylation reportedly increases during proestrus or upon acute leptin exposure during diestrus. To determine if nNOS S1412 regulates female reproduction in mice, we compared the reproductive anatomy, estrous cycle duration and phase proportion, and fecundity of wild-type and nNOS serine1412➔alanine (nNOSS1412A) knock-in female mice. We also measured hypothalamic GnRH and serum LH, follicle stimulating hormone (FSH), estradiol, and progesterone in diestrus mice after intraperitoneal leptin injection. Organ weights and histology were not different by genotype. Ovarian primordial follicles, antral follicles, and corpora lutea were similar for wild-type and nNOSS1412A mice. Likewise, estrous cycle duration and phase length were not different, and fecundity was unremarkable. There were no differences among genotypes for LH, FSH, estradiol, or progesterone. In contrast to prior studies, our work suggests that nNOS S1412 phosphorylation is dispensable for normal hypothalamic–pituitary–ovarian function and regular estrous cycling. These findings have important implications for current models of fertility regulation by nNOS phosphorylation.
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Semaan, Sheila J., Elaine K. Murray, Matthew C. Poling, Sangeeta Dhamija, Nancy G. Forger, and Alexander S. Kauffman. "BAX-Dependent and BAX-Independent Regulation of Kiss1 Neuron Development in Mice." Endocrinology 151, no. 12 (October 6, 2010): 5807–17. http://dx.doi.org/10.1210/en.2010-0783.
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The Kiss1 gene and its product kisspeptin are important regulators of reproduction. In rodents, Kiss1 is expressed in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV)/rostral periventricular (PeN) nuclei. In the AVPV/PeN, females have more Kiss1 and tyrosine hydroxylase (TH) neurons than males. We explored the ontogeny of the Kiss1 sex difference, and the role of cell death in establishing Kiss1 and TH cell number. We also determined whether Kiss1 cells in AVPV/PeN coexpress TH. AVPV/PeN Kiss1 neurons were first detected in both sexes on postnatal d 10, but the Kiss1 sex difference did not emerge until postnatal d 12. The role of BAX-mediated apoptosis in generating this sex difference was tested in adult Bax knockout (KO) and wild-type mice. Deletion of Bax did not diminish the sex difference in Kiss1 expression in the AVPV/PeN. TH expression was sexually dimorphic in the AVPV of both wild-type and Bax KO mice but, unlike Kiss1, was not sexually dimorphic in the PeN of either genotype. Double-label analysis determined that most Kiss1 neurons coexpress TH mRNA, but many TH neurons do not coexpress Kiss1, especially in the PeN. These findings suggest that several subpopulations of TH cells reside within the AVPV/PeN, only one of which coexpresses Kiss1. In the ARC, Kiss1 cell number was markedly increased in Bax KO mice of both sexes, indicating that although BAX-dependent apoptosis does not generate the sex difference in either Kiss1 or TH expression in AVPV/PeN, BAX does importantly regulate Kiss1 cell number in the ARC.
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Shaha, Chandrima, Rakshamani Tripathi, and Durga Prasad Mishra. "Male germ cell apoptosis: regulation and biology." Philosophical Transactions of the Royal Society B: Biological Sciences 365, no. 1546 (May 27, 2010): 1501–15. http://dx.doi.org/10.1098/rstb.2009.0124.
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Cellular apoptosis appears to be a constant feature in the adult testis and during early development. This is essential because mammalian spermatogenesis is a complex process that requires precise homeostasis of different cell types. This review discusses the latest information available on male germ cell apoptosis induced by hormones, toxins and temperature in the context of the type of apoptotic pathway either the intrinsic or the extrinsic that may be used under a variety of stimuli. The review also discusses the importance of mechanisms pertaining to cellular apoptosis during testicular development, which is independent of exogenous stimuli. Since instances of germ cell carcinoma have increased over the past few decades, the current status of research on apoptotic pathways in teratocarcinoma cells is included. One other important aspect that is covered in this review is microRNA-mediated control of germ cell apoptosis, a field of research that is going to see intense activity in near future. Since knockout models of various kinds have been used to study many aspects of germ cell development, a comprehensive summary of literature on knockout mice used in reproduction studies is also provided.
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Meccariello, R., G. Berruti, R. Chianese, R. De Santis, F. Di Cunto, D. Scarpa, G. Cobellis, et al. "Structure of msj-1 gene in mice and humans: A possible role in the regulation of male reproduction." General and Comparative Endocrinology 156, no. 1 (March 2008): 91–103. http://dx.doi.org/10.1016/j.ygcen.2007.11.014.
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Proietto, S., S. A. Cortasa, M. C. Corso, P. I. F. Inserra, S. E. Charif, A. R. Schmidt, N. P. Di Giorgio, et al. "Prolactin Is a Strong Candidate for the Regulation of Luteal Steroidogenesis in Vizcachas (Lagostomus maximus)." International Journal of Endocrinology 2018 (June 14, 2018): 1–14. http://dx.doi.org/10.1155/2018/1910672.
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Prolactin (PRL) is essential for the maintenance of the corpora lutea and the production of progesterone (P4) during gestation of mice and rats, which makes it a key factor for their successful reproduction. Unlike these rodents and the vast majority of mammals, female vizcachas (Lagostomus maximus) have a peculiar reproductive biology characterized by an ovulatory event during pregnancy that generates secondary corpora lutea with a consequent increment of the circulating P4. We found that, although the expression of pituitary PRL increased steadily during pregnancy, its ovarian receptor (PRLR) reached its maximum in midpregnancy and drastically decreased at term pregnancy. The luteinizing hormone receptor (LHR) exhibited a similar profile than PRLR. Maximum P4 and LH blood levels were recorded at midpregnancy as well. Remarkably, the P4-sinthesizing enzyme 3β-HSD accompanied the expression pattern of PRLR/LHR throughout gestation. Instead, the luteolytic enzyme 20α-HSD showed low expression at early and midpregnancy, but reached its maximum at the end of gestation, when PRLR/LHR/3ß-HSD expressions and circulating P4 were minimal. In conclusion, both the PRLR and LHR expressions in the ovary would define the success of gestation in vizcachas by modulating the levels of 20α-HSD and 3ß-HSD, which ultimately determine the level of serum P4 throughout gestation.
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Boisen, Ida Marie, John Erik Nielsen, Lieve Verlinden, Mette Lorenzen, Rune Holt, Anja Pinborg, Christine Hjorth Andreassen, et al. "Calcium transport in male reproduction is possibly influenced by vitamin D and CaSR." Journal of Endocrinology 251, no. 3 (December 1, 2021): 207–22. http://dx.doi.org/10.1530/joe-20-0321.
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Vitamin D is important for gonadal function in rodents, and improvement of vitamin D status in men with low sperm counts increases live birth rate. Vitamin D is a regulator of transcellular calcium transport in the intestine and kidney and may influence the dramatic changes in the luminal calcium concentration in epididymis. Here, we show spatial expression in the male reproductive tract of vitamin D receptor (VDR)-regulated factors involved in calcium transport: transient receptor potential vanilloid 5/6 , sodium/calcium exchanger 1, plasma membrane calcium ATPase 1, calbindin D9k, calcium-sensing receptor (CaSR), and parathyroid hormone-related peptide (PTHrP) in mouse and human testis and epididymis. Testicular Casr expression was lower in Vdr ablated mice compared with controls. Moreover, expression levels of Casr and Pthrp were strongly correlated in both testis and epididymis and Pthrp was suppressed by 1,25(OH)2D3 in a spermatogonial cell line. The expression of CaSR in epididymis may be of greater importance than in the gonad in mice as germ cell-specific Casr deficient mice had no major reproductive phenotype, and coincubation with a CaSR-agonist had no effect on human sperm–oocyte binding. In humans, seminal calcium concentration between 5 and 10 mM was associated with a higher fraction of motile and morphologically normal sperm cells, and the seminal calcium concentration was not associated with serum calcium levels. In conclusion, VDR regulates CaSR and PTHrP, and both factors may be involved in the regulation of calcium transport in the male reproductive tract with possible implications for sperm function and storage.
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Withers, D. J. "Insulin receptor substrate proteins and neuroendocrine function." Biochemical Society Transactions 29, no. 4 (August 1, 2001): 525–29. http://dx.doi.org/10.1042/bst0290525.
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A family of insulin receptor substrate (IRS) proteins mediates the pleiotropic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. Conventional murine knockout strategies have started to reveal distinct physiological roles for the IRS proteins. Deletion of Irsl produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. In contrast, mice lacking IRS-2 display nearly normal growth but develop diabetes owing to a combination of peripheral insulin resistance and β-cell failure. As well as the classical metabolic events regulated by insulin signalling pathways, studies in lower organisms have implicated insulin/IGF-1 signalling pathways in the control of food intake and reproductive function. Our analysis of IRS-2 knockout mice shows that female mice are infertile owing to defects in the hypothalamus, pituitary and gonad. IRS-2−1 mice have small, anovulatory ovaries with reduced numbers of follicles. Levels of the pituitary hormones luteinizing hormone and prolactin and gonadal steroids are low in these animals. Pituitaries of IRS-2−1 animals are decreased in size and contain reduced numbers of gonadotrophs. Additionally, IRS-2−1 females display increased food intake and develop obesity, despite elevated leptin levels, suggesting abnormalities in hypothalamic function. Coupled with recent observations that brain-specific deletion of the insulin receptor causes a similar phenotype, these findings implicate IRS signalling pathways in the neuroendocrine regulation of reproduction and energy homeostasis.
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Carretero, Jose, Francisco López, Leonardo Catalano-Iniesta, Virginia Sanchez-Robledo, Maria Jose Garcia-Barrado, Maria Carmen Iglesias-Osma, Marta Carretero-Hernandez, Enrique J. Blanco, and Deborah Jane Burks. "Pituitary Aromatase P450 May Be Involved in Maintenance of the Population of Luteinizing Hormone-Positive Pituitary Cells in Mice." Cells Tissues Organs 201, no. 5 (2016): 390–98. http://dx.doi.org/10.1159/000445478.
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As aromatase P450 is located in several pituitary cells, testosterone can be transformed into 17β-estradiol in the gland by the enzyme. The possible role of this transformation in pituitary function remains to be elucidated, but some evidence suggests a physiological and pathophysiological role for pituitary aromatase. To determine its relevance in the modulation of pituitary function, mainly associated with reproduction, luteinizing hormone (LH)-positive cells in the hypophysis of female and male aromatase knockout (ArKO) mice were studied. In all LH-positive cells, significant increases in the cellular (p < 0.01) and nuclear (p < 0.05) areas were found in the ArKO mice compared to the wild-type mice. In the ArKO mice, LH-positive cells were more abundant (p < 0.01); they were characterized by a stronger cytoplasmic reaction and the cells were more polygonal and exhibited more short, thick cytoplasmic prolongations than those in the wild-type mice. Moreover, LH-positive cells showed a greater proliferation rate in the ArKO mice compared to the wild-type mice (p < 0.01). These findings suggest that the local production of estradiol mediated by pituitary aromatase is necessary for the regulation of LH-positive gonadotropic cells, exerting an autoparacrine inhibitory regulation. These results could underlie the higher pituitary aromatase expression observed in male versus female mice. Similar effects were found in ArKO male and female mice, suggesting that in both sexes the effects of estrogens on maintenance of the LH-positive pituitary cell population could be related to the local aromatization of testosterone to estradiol inside the hypophysis. Therefore, aromatase could modulate pituitary LH-positive cells in males through local estradiol synthesis.
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Craythorn, R. G., W. R. Winnall, M. P. Hedger, P. A. W. Rogers, D. M. De Kretser, and J. E. Girling. "308. FOLLISTATIN SPLICE VARIANTS FST288 AND FST315 INCREASE DURING EARLY MOUSE PREGNANCY: REGULATION BY PROGESTERONE?" Reproduction, Fertility and Development 22, no. 9 (2010): 108. http://dx.doi.org/10.1071/srb10abs308.
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Follistatin acts by binding and neutralising the activity of activin-A, which has important regulatory roles in development, reproduction and inflammation. There are two isoforms of follistatin comprising 288 and 315 amino acids (FST288 and FST315), resulting from alternative gene splicing. FST288 binds spontaneously to heparan sulphate and is largely bound to cell surface proteoglycans. FST315 is the predominant circulating form and can only bind to heparan sulphate after binding activin-A. The regulation of these splice variants in the female reproductive tract have not been investigated in detail. In this study, our aim was to quantify the expression of FST288 and FST315 mRNA in the mouse uterus during early pregnancy (days 1–4, pre-implantation), and in response to exogenous oestradiol-17b (100 ng × single s.c. injection, dissection after 24 h) and progesterone (1 mg × three daily s.c. injections, dissection 24 h after last injection) in ovariectomised mice. Gene expression was analysed using quantitative RT-PCR. Primers amplifying a product from exon 5 to 6a (unique to FST288) or from exon 5 to 6b (unique to FST315) were used to discriminate the isoforms. In early pregnancy, expression of both FST288 and FST315 increased significantly (approximately 35-fold and 100-fold, respectively) on days 3–5, relative to days 1–2, corresponding with the increase in circulating progesterone levels that occurs at day 3. A significant increase in FST288 and FST315 mRNA expression (both approximately 35-fold) was also observed in ovariectomised mice in response to exogenous progesterone, but there was no increase in response to oestradiol-17β. In contrast to the similar rate of increase in response to exogenous progesterone, FST315 mRNA expression increased more rapidly than FS288 in early pregnancy, indicating that differential regulation of the two isoforms also occurs. We conclude that progesterone regulates both FST288 and FST315 mRNA expression during early pregnancy in the mouse uterus.
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Luque, Raul M., Rhonda D. Kineman, and Manuel Tena-Sempere. "Regulation of Hypothalamic Expression of KiSS-1 and GPR54 Genes by Metabolic Factors: Analyses Using Mouse Models and a Cell Line." Endocrinology 148, no. 10 (October 1, 2007): 4601–11. http://dx.doi.org/10.1210/en.2007-0500.
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It is well established that reproductive function is metabolically gated. However, the mechanisms whereby energy stores and metabolic cues influence fertility are yet to be completely deciphered. Recently, the hypothalamic KiSS-1/GPR54 system has emerged as a fundamental regulator of the gonadotropic axis, which conveys the modulatory actions of sex steroids to GnRH neurons. Evidence is also mounting that KiSS-1 neurons may also represent the link between systemic metabolic signals and central control of reproduction. To further explore this possibility, we examined the impact of changes in energy status and key metabolic regulators on the hypothalamic expression of KiSS-1 and GPR54 genes, using different mouse models and the hypothalamic cell line N6. Time-course analysis of the effects of short-term fasting revealed a rapid (12- and 24-h) decline in KiSS-1 and GPR54 mRNA levels, which preceded that of GnRH (48 h). In contrast, diet-induced obesity or obesity associated with leptin deficiency (ob/ob vs. wild-type mice) failed to induce overt changes in hypothalamic expression of KiSS-1 and GPR54 genes. However, leptin infusion of ob/ob mice evoked a significant increase in KiSS-1 and GPR54 mRNA levels compared with pair-fed controls. Moreover, leptin, but not insulin or IGF-I, stimulated KiSS-1 mRNA expression in the mouse hypothalamic cell line N6. In addition, neuropeptide Y (NPY) null mice showed decreased KiSS-1 mRNA levels at the hypothalamus, whereas exposure to NPY increased expression of KiSS-1 in hypothalamic N6 cells. In sum, our present data further characterize the functional relevance and putative key mediators (such as leptin and NPY) of the metabolic regulation of the hypothalamic KiSS-1 system in the mouse.