RESUMEN
Female puberty is subject to Polycomb Group (PcG)-dependent transcriptional repression. Kiss1, a puberty-activating gene, is a key target of this silencing mechanism. Using a gain-of-function approach and a systems biology strategy we now show that EED, an essential PcG component, acts in the arcuate nucleus of the hypothalamus to alter the functional organization of a gene network involved in the stimulatory control of puberty. A central node of this network is Kdm6b, which encodes an enzyme that erases the PcG-dependent histone modification H3K27me3. Kiss1 is a first neighbor in the network; genes encoding glutamatergic receptors and potassium channels are second neighbors. By repressing Kdm6b expression, EED increases H3K27me3 abundance at these gene promoters, reducing gene expression throughout a gene network controlling puberty activation. These results indicate that Kdm6b repression is a basic mechanism used by PcG to modulate the biological output of puberty-activating gene networks.
Asunto(s)
Histona Demetilasas con Dominio de Jumonji/genética , Kisspeptinas/genética , Complejo Represivo Polycomb 2/genética , Pubertad/genética , Animales , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Humanos , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Neuronas/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Proteínas del Grupo Polycomb/genética , Regiones Promotoras Genéticas/genética , Pubertad/fisiología , Ratas , Biología de SistemasRESUMEN
Research into the physiological actions of anti-Müllerian hormone (AMH) has rapidly expanded from its classical role in male sexual differentiation to the regulation of ovarian function, routine clinical use in reproductive health and potential use as a biomarker in the diagnosis of polycystic ovary syndrome (PCOS). During the past 10 years, the notion that AMH could act exclusively at gonadal levels has undergone another paradigm shift as several exciting studies reported unforeseen AMH actions throughout the Hypothalamic-Pituitary-Gonadal (HPG) axis. In this review, we will focus on these findings reporting novel AMH actions across the HPG axis and we will discuss their potential impact and significance to better understand human reproductive disorders characterized by either developmental alterations of neuroendocrine circuits regulating fertility and/or alterations of their function in adult life. Finally, we will summarize recent preclinical studies suggesting that elevated levels of AMH may potentially be a contributing factor to the central pathophysiology of PCOS and other reproductive diseases.
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Hormona Antimülleriana/metabolismo , Gónadas/metabolismo , Hipotálamo/metabolismo , Hipófisis/metabolismo , Femenino , Humanos , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/patología , Reproducción , Transducción de SeñalRESUMEN
The timing of pubertal attainment in gilts is a critical factor for pork production and is an early indicator of future reproductive potential. Puberty, defined as age at first standing estrus in the presence of a boar, is brought about by an escape from estrogen inhibition of the GnRH pulse generator, which allows for increasing LH pulses leading to the onset of cyclicity. The biological mechanisms that control the timing of these events is related to decreasing inhibitory signals with a concomitant increase in stimulatory signals within the hypothalamus. The roles of gamma-aminobutyric acid, endogenous opioid peptides, and gonadotropin-inhibitory hormone in negatively regulating gonadotropin secretion in gilts is explored. Developmental changes in stimulatory mechanisms of glutamatergic and kisspeptin neurons are important for increased LH pulsatility required for the occurrence of puberty in pigs. Age at first estrus of gilts is metabolically gated, and numerous metabolites, metabolic hormones, and appetite-regulating neurotransmitters have been implicated in the nutritional regulation of gonadotropin secretion. Leptin is an important metabolic signal linking body energy reserves with age at puberty in gilts. Leptin acting through neuropeptide Y and proopiomelanocortin neurons in the hypothalamus has important impacts on the function of the reproductive neurosecretory axis of gilts. Age at puberty in swine is heritable, and genomic analyses reveal it to be a polygenic trait. Genome-wide association studies for pubertal age in gilts have revealed several genomic regions in common with those identified for age at menarche in humans. Candidate genes have been identified that have important functions in growth and adiposity. Numerous genes regulating hypothalamic neuronal function, gonadotropes in the adenohypophysis, and ovarian follicular development have been identified and illustrate the complex maturational changes occurring in the hypothalamic-pituitary-ovarian axis during puberty in gilts.
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Genómica , Sistemas Neurosecretores/crecimiento & desarrollo , Maduración Sexual/fisiología , Porcinos/fisiología , Animales , Femenino , Estudio de Asociación del Genoma Completo , Porcinos/genéticaRESUMEN
Developmental programming refers to processes that occur during early life that may have long-term consequences, modulating adult health and disease. Complex diseases, such as diabetes, cancer and cardiovascular disease, have a high prevalence in different populations, are multifactorial, and may have a strong environmental component. The environment interacts with organisms, affecting their behaviour, morphology and physiology. This interaction may induce permanent or long-term changes, and organisms may be more susceptible to environmental factors during certain developmental stages, such as the prenatal and early postnatal periods. Several factors have been identified as responsible for inducing the reprogramming of various reproductive and nonreproductive tissues. Among them, both natural and synthetic steroids, such as endocrine disruptors, are known to have either detrimental or positive effects on organisms depending on the dose of exposure, stage of development and biological sexual background. The present review focuses on the action of steroids and endocrine disruptors as agents involved in developmental programming and on their modulation and effects on female neuroendocrine functions.
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Disruptores Endocrinos/toxicidad , Hormonas Esteroides Gonadales/fisiología , Sistemas Neurosecretores/crecimiento & desarrollo , Animales , Femenino , Humanos , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/fisiopatología , Síndrome del Ovario Poliquístico/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatologíaRESUMEN
The semaphorin proteins, which contribute to the morphogenesis and homeostasis of a wide range of systems, are among the best-studied families of guidance cues. Much recent research has focused on the role of semaphorins in the development and adult activity of hormone systems and, reciprocally, how circulating reproductive hormones regulate their expression and function. Specifically, several reports have focused on the molecular mechanisms underlying the effects of semaphorins on the migration, survival and structural and functional plasticity of neurons that secrete gonadotropin-releasing hormone (GnRH), essential for the acquisition and maintenance of reproductive competence in mammals. Alterations in the development of this neuroendocrine system lead to anomalous or absent GnRH secretion, resulting in heterogeneous reproductive disorders such as congenital hypogonadotropic hypogonadism (CHH) or other conditions characterized by infertility or subfertility. This review summarizes current knowledge of the role of semaphorins and their receptors on the development, differentiation and plasticity of the GnRH system. In addition, the involvement of genetic deficits in semaphorin signaling in some forms of CHH in humans is discussed.
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Hormona Liberadora de Gonadotropina/metabolismo , Neuronas/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Fenómenos Fisiológicos Reproductivos , Semaforinas/metabolismo , Animales , Movimiento Celular , Humanos , Sistemas Neurosecretores/embriología , Vías Olfatorias/embriología , Vías Olfatorias/crecimiento & desarrollo , Vías Olfatorias/metabolismo , Prosencéfalo/embriología , Prosencéfalo/crecimiento & desarrollo , Prosencéfalo/metabolismo , Transducción de SeñalRESUMEN
Dopaminergic (DA) neurons located in the preoptico-hypothalamic region of the brain exert a major neuroendocrine control on reproduction, growth, and homeostasis by regulating the secretion of anterior pituitary (or adenohypophysis) hormones. Here, using a retrograde tract tracing experiment, we identified the neurons playing this role in the zebrafish. The DA cells projecting directly to the anterior pituitary are localized in the most anteroventral part of the preoptic area, and we named them preoptico-hypophyseal DA (POHDA) neurons. During development, these neurons do not appear before 72 hours postfertilization (hpf) and are the last dopaminergic cell group to differentiate. We found that the number of neurons in this cell population continues to increase throughout life proportionally to the growth of the fish. 5-Bromo-2'-deoxyuridine incorporation analysis suggested that this increase is due to continuous neurogenesis and not due to a phenotypic change in already-existing neurons. Finally, expression profiles of several genes (foxg1a, dlx2a, and nr4a2a/b) were different in the POHDA compared with the adjacent suprachiasmatic DA neurons, suggesting that POHDA neurons develop as a distinct DA cell population in the preoptic area. This study offers some insights into the regional identity of the preoptic area and provides the first bases for future functional genetic studies on the development of DA neurons controlling anterior pituitary functions.
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Neuronas Dopaminérgicas/fisiología , Neurogénesis/fisiología , Adenohipófisis/fisiología , Pez Cebra/anatomía & histología , Pez Cebra/crecimiento & desarrollo , Animales , Animales Modificados Genéticamente , Neuronas Dopaminérgicas/citología , Embrión no Mamífero , Femenino , Sistemas Neurosecretores/citología , Sistemas Neurosecretores/crecimiento & desarrollo , Adenohipófisis/embriología , Adenohipófisis/crecimiento & desarrollo , Hormonas Adenohipofisarias/metabolismo , Área Preóptica/embriología , Área Preóptica/crecimiento & desarrollo , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
Testis growth during early life is important for future male fertility and shows acceleration during the first months of life in humans. This acceleration coincides with the peak in gonadotropic hormones in the blood, while the role of hypothalamic factors remains vague. Using neonatal rats to assess this issue, we found that day 9 of life is likely critical for testis development in rats. Before this day, testicular growth was proportional to body weight gain, but after that the testes showed accelerated growth. Hypothalamic kisspeptin and its receptor mRNA levels begin to elevate 2 days later, at day 11. A significant increase in the mRNA levels for gonadotropin-releasing hormone (GnRH) receptors in the hypothalamus between days 5 and 7 was followed by a 3-fold decrease in GnRH mRNA levels in this brain region during the next 2 days. Starting from day 9, hypothalamic GnRH mRNA levels increased significantly and positively correlated with accelerated testicular growth. Triptorelin, an agonist of GnRH, at a dose that had no effect on testicular growth during "proportional" period, increased testis weights during the period of accelerated growth. The insensitivity of testicular growth to GnRH during "proportional" period was supported by inability of a 2.5-fold siRNA knockdown of GnRH expression in the hypothalamus of the 7-day-old animals to produce any effect on their testis weights. GnRH receptor blockade with cetrorelix was also without effect on testis weights during "proportional" period but the same doses of this GnRH antagonist significantly inhibited "accelerated" testicular growth. GnRH receptor mRNA levels in the pituitary as well as plasma LH concentrations were higher during "accelerated" period of testicular growth than during "proportional" period. In general, our data defined two distinct periods in rat testicular development that are primarily characterized by different responses to GnRH signaling.
Asunto(s)
Envejecimiento/fisiología , Hormonas Gonadales/metabolismo , Hipotálamo/metabolismo , Sistemas Neurosecretores/crecimiento & desarrollo , Testículo/crecimiento & desarrollo , Envejecimiento/efectos de los fármacos , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Kisspeptinas/metabolismo , Luteolíticos/farmacología , Masculino , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptores LHRH/biosíntesis , Transducción de Señal , Pamoato de Triptorelina/farmacologíaRESUMEN
The paraventricular nucleus of the hypothalamus (PVH) consists of distinct functional compartments regulating neuroendocrine, behavioral, and autonomic activities that are involved in the homeostatic control of energy balance. These compartments receive synaptic inputs from neurons of the arcuate nucleus of the hypothalamus (ARH) that contains orexigenic agouti-related peptide (AgRP) and anorexigenic pro-opiomelanocortin (POMC) neuropeptides. The axon outgrowth from the ARH to PVH occurs during a critical postnatal period and is influenced by the adipocyte-derived hormone leptin, which promotes its development. However, little is known about leptin's role in specifying patterns of cellular connectivity in the different compartments of the PVH. To address this question, we used retrograde and immunohistochemical labeling to evaluate neuronal inputs onto sympathetic preautonomic and neuroendocrine neurons in PVH of leptin-deficient mice (Lep(ob)/Lep(ob)) exposed to a postnatal leptin treatment. In adult Lep(ob)/Lep(ob) mice, densities of AgRP- and α-melanocortin stimulating hormone (αMSH)-immunoreactive fibers were significantly reduced in neuroendocrine compartments of the PVH, but only AgRP were reduced in all regions containing preautonomic neurons. Moreover, postnatal leptin treatment significantly increased the density of AgRP-containing fibers and peptidergic inputs onto identified preautonomic, but not onto neuroendocrine cells. Neonatal leptin treatment neither rescued αMSH inputs onto neuroendocrine neurons, nor altered cellular ratios of inhibitory and excitatory inputs. These effects were associated with attenuated body weight gain, food intake and improved physiological response to sympathetic stimuli. Together, these results provide evidence that leptin directs cell type-specific patterns of ARH peptidergic inputs onto preautonomic neurons in the PVH, which contribute to normal energy balance regulation.
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Animales Recién Nacidos/fisiología , Hipotálamo/crecimiento & desarrollo , Leptina/deficiencia , Leptina/farmacología , Sistema Nervioso Parasimpático/crecimiento & desarrollo , Tejido Adiposo Pardo/citología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/citología , Tejido Adiposo Blanco/efectos de los fármacos , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/genética , Regulación de la Temperatura Corporal/fisiología , Peso Corporal/fisiología , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Ácido Glutámico/fisiología , Hipotálamo/citología , Hipotálamo/efectos de los fármacos , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Leptina/genética , Masculino , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Sistemas Neurosecretores/citología , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/crecimiento & desarrollo , Sistema Nervioso Parasimpático/citología , Sistema Nervioso Parasimpático/efectos de los fármacos , Péptidos/fisiología , Ácido gamma-Aminobutírico/fisiologíaRESUMEN
BACKGROUND: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS. METHODS: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity. RESULTS: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood. CONCLUSIONS: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.
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Modelos Animales de Enfermedad , Glándulas Endocrinas/inervación , Genitales Femeninos/inervación , Hiperandrogenismo/fisiopatología , Sistemas Neurosecretores , Síndrome del Ovario Poliquístico/etiología , Maduración Sexual , Andrógenos/administración & dosificación , Andrógenos/efectos adversos , Andrógenos/sangre , Animales , Glándulas Endocrinas/efectos de los fármacos , Glándulas Endocrinas/crecimiento & desarrollo , Femenino , Genitales Femeninos/efectos de los fármacos , Genitales Femeninos/crecimiento & desarrollo , Hormona Liberadora de Gonadotropina/metabolismo , Resistencia a la Insulina , Hormona Luteinizante/sangre , Hormona Luteinizante/metabolismo , Macaca mulatta , Menarquia/efectos de los fármacos , Ciclo Menstrual/sangre , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/crecimiento & desarrollo , Obesidad/fisiopatología , Ovario/diagnóstico por imagen , Ovario/crecimiento & desarrollo , Ovulación/efectos de los fármacos , Hipófisis/crecimiento & desarrollo , Hipófisis/metabolismo , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/metabolismo , Maduración Sexual/efectos de los fármacos , Testosterona/administración & dosificación , Testosterona/efectos adversos , Testosterona/sangre , UltrasonografíaRESUMEN
Neonatal exposure to endocrine disrupting chemicals (EDCs) such as polychlorinated biphenyls (PCBs) can interfere with hormone-sensitive developmental processes, including brain sexual differentiation. We hypothesized that disruption of these processes by gestational PCB exposure would be detectable as early as the day after birth (postnatal day (P) 1) through alterations in hypothalamic gene and protein expression. Pregnant Sprague-Dawley rats were injected twice, once each on gestational days 16 and 18, with one of the following: DMSO vehicle; the industrial PCB mixture Aroclor 1221 (A1221); a reconstituted mixture of the three most prevalent congeners found in humans, PCB138, PCB153, and PCB180; or estradiol benzoate (EB). On P1, litter composition, anogenital distance (AGD), and body weight were assessed. Pups were euthanized for immunohistochemistry of estrogen receptor α (ERα) or TUNEL labeling of apoptotic cells or quantitative PCR of 48 selected genes in the preoptic area (POA). We found that treatment with EB or A1221 had a sex-specific effect on developmental apoptosis in the neonatal anteroventral periventricular nucleus (AVPV), a sexually dimorphic hypothalamic region involved in the regulation of reproductive neuroendocrine function. In this region, exposed females had increased numbers of apoptotic nuclei, whereas there was no effect of treatment in males. For ERα, EB treatment increased immunoreactive cell numbers and density in the medial preoptic nucleus (MPN) of both males and females, while A1221 and the PCB mixture had no effect. PCR analysis of gene expression in the POA identified nine genes that were significantly altered by prenatal EDC exposure, in a manner that varied by sex and treatment. These genes included brain-derived neurotrophic factor, GABA(B) receptors-1 and -2, IGF-1, kisspeptin receptor, NMDA receptor subunits NR2b and NR2c, prodynorphin, and TGFα. Collectively, these results suggest that the disrupted sexual differentiation of the POA by prenatal EDC exposures is already evident as early as the day after birth, effects that may change the trajectory of postnatal development and compromise adult reproductive function.
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Disruptores Endocrinos/toxicidad , Hipotálamo/efectos de los fármacos , Hipotálamo/crecimiento & desarrollo , Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Factores de Edad , Animales , Animales Recién Nacidos , Femenino , Hipotálamo/embriología , Masculino , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Embarazo , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyAsunto(s)
Envejecimiento/fisiología , Homeostasis/fisiología , Hipotálamo/fisiología , Sistemas Neurosecretores/fisiología , Envejecimiento/metabolismo , Animales , Dopamina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Neuronas/metabolismo , Neuronas/fisiología , Neurosecreción/fisiología , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Ratas , Serotonina/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Recently it has been proven that non-small cell lung cancer (NSCLC) also had the feature of neuroendocrine (NE) differentiation. The aim of this study is to investigate the correlation between NE differentiation of NSCLC and its biological behaviors, together with prognosis. METHODS: All NSCLC paraffin-embedded specimens and cases, followed up over than 3 years, were randomly obtained from 206 patients from January 2005 to December 2007, who underwent surgical resection and confirmed pathologically. All of them were not underwent radiation and chemotherapy before operation. Immunohistochemical Envision two-step method was used to detect the expressions of NSE, CgA and Syn. And all data were analyzed using SPSS statistics software and Kaplan-Meier survival curves were constructed, and Log-rank test was also conducted. RESULTS: Of the 206 patients, 84 cases with NE differentiation (39.8%) and CgA, NSE and Syn positive rates were 53 (25.7%), 104 (50.5%), 91 (44.2%) respectively; a statistically significant difference between NSCLC with NE differentiation were showed. The positive expression of Syn was closely correlated with histological differentiation, lymph node metastasis. The survival of single-factor analysis by the Log-rank test showed that Syn had relation to the postoperative survival rate of patients (Chi2=4.164, P=0.041), while the relevance between patients with NE and survival had no significant difference (P>0.05). CONCLUSIONS: NE differentiation is an important indicator of biological behavior of NSCLC; and the detection of Syn markers of neuroendocrine differentiation may be recommended to detect NE differentiation of NSCLC, and the positive expression of Syn suggests poor prognosis.
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Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Sistemas Neurosecretores/metabolismo , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Cromogranina A/genética , Cromogranina A/metabolismo , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Metástasis Linfática , Masculino , Persona de Mediana Edad , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/patología , Fosfopiruvato Hidratasa/genética , Fosfopiruvato Hidratasa/metabolismo , Pronóstico , Sinaptofisina/genética , Sinaptofisina/metabolismoRESUMEN
The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed.
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Disruptores Endocrinos/toxicidad , Epigenómica , Infertilidad Femenina/inducido químicamente , Ovario/efectos de los fármacos , Animales , Contaminantes Ambientales/toxicidad , Femenino , Perfilación de la Expresión Génica , Genitales Femeninos/efectos de los fármacos , Genitales Femeninos/crecimiento & desarrollo , Humanos , Infertilidad Femenina/genética , Masculino , Ratones , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/crecimiento & desarrollo , Ovario/crecimiento & desarrollo , Receptores Androgénicos/análisis , Receptores de Estrógenos/análisis , Útero/efectos de los fármacos , Útero/crecimiento & desarrolloRESUMEN
The maintaining of homeostasis in the organism in response to a variable environment is provided by the highly hierarchic neuroendocrine-immune system. The crucial component of this system is the hypothalamus providing the endocrine regulation of key peripheral organs, and the adenohypophysis. In this case, neuron-derived signaling molecules (SM) are delivered to the blood vessels in hypothalamic "neurohaemal organs" lacking the blood-brain barrier (BBB), the posterior lobe of the pituitary and the median eminence. The release of SM to the blood vessels in most other brain regions is prohibited by BBB. According to the conventional concept, the development of the neuroendocrine system in ontogenesis begins with the "maturation" of peripheral endocrine glands which first are self-governed and then operate under the adenohypophysial control. Meantime, the brain maturation is under the control of SM secreted by endocrine glands of the developing organism and coming from the placenta and maternal organism. The hypothalamus is involved in the neuroendocrine regulation only after its full maturation that is followed by the conversion of the opened-looped neuroendocrine system to the closed-looped system as in adulthood. Neurons of the developing brain begin to secrete SM shortly after their origin and long before the establishment of specific interneuronal relations providing initially autocrine and paracrine morphogenetic influence on differentiating target neurons. Taking into account that the brain lacks BBB over this ontogenetic period, we hypothesized that it operates as the multipotent endocrine gland secreting SM to the general circulation and thereby providing the endocrine regulation of peripheral organs and the brain. The term "multipotent" means that the spectrum of the brain-derived circulating SM and their occupancy at the periphery in the developing organism should greatly exceed those in adulthood. In order to test this hypothesis, gonadotropin-releasing hormone (GnRH), dopamine (DA), and serotonin (5-hydroxytryptamine, 5-HT) were chosen as the markers of the presumptive endocrine function of the brain in ontogenesis. According to our data, the concentrations of GnRH, DA, and 5-HT in the rat general circulation during the perinatal period, i.e. before the establishment of BBB, was as high as those in the portal circulation in adulthood. The concentrations of circulating GnRH and DA dropped to almost undetectable level after the development of BBB suggesting their brain origin. This suggestion has been proven by showing an essential decrease of GnRH, DA, and 5-HT concentrations in general circulation of perinatal rats after microsurgical elimination of synthesizing neurons or the inhibition of specific syntheses in the brain before the establishment of BBB. GnRH, DA, and 5-HT apparently as dozens of other brain-derived SM appear to be capable of providing the endocrine influence on their peripheral targets like the adenohypophysis, gonads, kidney, heart, blood vessels, and the brain (endocrine autoregulation). Although the ontogenetic period of the brain operation as the multipotent endocrine gland is relatively short, the brain-derived SM are thought to be capable of providing long-lasting morphogenetic effects on peripheral targets and the brain. Thus, the developing brain operates as the multipotent endocrine gland from the onset of neurogenesis to the establishment of BBB providing the endocrine regulation of the developing organism.
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Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Animales , Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/crecimiento & desarrollo , Barrera Hematoencefálica/fisiología , Encéfalo/fisiología , Dopamina/sangre , Hormona Liberadora de Gonadotropina/sangre , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiología , Neurogénesis , Sistemas Neurosecretores/fisiología , Ratas , Serotonina/sangreRESUMEN
The protein interacting with C kinase 1 (PICK1) protein was first identified as a novel binding partner for protein kinase C. PICK1 contains a membrane-binding BAR domain and a PDZ domain interacting with many synaptic proteins, including the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit GluR2 and the dopamine transporter. PICK1 is strongly implicated in GluR2 trafficking and synaptic plasticity. In mammals, PICK1 has been characterized extensively in cell culture studies. To study PICK1 in an intact system, we characterized PICK1 expression immunohistochemically in the adult and larval Drosophila central nervous system. PICK1 was found in cell bodies in the subesophageal ganglion, the antennal lobe, the protocerebrum, and the neuroendocrine center pars intercerebralis. The cell types that express PICK1 were identified using GAL4 enhancer trap lines. The PICK1-expressing cells form a subpopulation of neurons. PICK1 immunoreactivity was neither detected in glutamatergic nor in dopaminergic neurons. Also, we observed PICK1 expression in only a few GABAergic neurons, located in the antennal lobe. In contrast, we detected robust PICK1 immunolabeling of peptidergic neurons in the neuroendocrine system, which express the transcription factor DIMM and the amidating enzyme peptidylglycine-alpha-hydroxylating monooxygenase (PHM). The PICK1-positive cells include neurosecretory cells that produce the insulin-like peptide dILP2. PICK1 expression in insulin-producing cells also occurs in mammals, as it was also observed in a rat insulinoma cell line derived from pancreatic beta-cells. At the subcellular level, PICK1 was found in the perinuclear zone but surprisingly not in synaptic domains. We conclude that PICK1 may serve an important role in the neuroendocrine system both in insects and vertebrates.
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Proteínas Portadoras/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Células Neuroendocrinas/metabolismo , Neuronas/metabolismo , Animales , Animales Modificados Genéticamente , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Proteínas Portadoras/genética , Línea Celular Tumoral , Dopamina/metabolismo , Proteínas de Drosophila/genética , Ácido Glutámico/metabolismo , Inmunohistoquímica , Larva/crecimiento & desarrollo , Larva/metabolismo , Mutación , Neuropéptidos , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Sistema Nervioso Periférico/crecimiento & desarrollo , Sistema Nervioso Periférico/metabolismo , Ratas , Médula Espinal/crecimiento & desarrollo , Médula Espinal/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Gastroenteropancreatic neuroendocrine tumours (GEP NETs) originate from the neuroendocrine cells through the gastrointestinal tract and endocrine pancreas. The embryologic development of the pancreas is a complex process that begins with the "stem cell" that come from the endodermus. These cells go through two phases: in the first transition the "stem cell" differentiates in exocrine and endocrine cells. This process is regulated by transcription factors such as Pdx1 ("insulin promoter factor 1"), Hlxb6 and SOX9. In the second transition the neuroendocrine cell differentiates in the 5 cell types (alpha, beta, delta, PP y epsilon.). This process is regulated through the balance between factors favoring differentiation (mainly neurogenin 3) and inhibitor factors which depend on Notch signals. The existence of a third transition in postnatal pancreas is hypothesized. The "stem cell" from pancreatic ducts would become adult beta cells, through autoduplication and neogenesis. In the small gut of the adult the stem cell are placed in the intestinal crypts and develop to villi in secretor lines (enterocytes, globet and Paneths cells) or neuroendocrine cells from which at least 10 cell types depend. This process is regulated by transcription factors: Math1, neurogenina 3 and NeuroD.
Asunto(s)
Tracto Gastrointestinal , Sistemas Neurosecretores , Animales , Tracto Gastrointestinal/embriología , Tracto Gastrointestinal/crecimiento & desarrollo , Humanos , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/crecimiento & desarrollo , Páncreas/embriología , Páncreas/crecimiento & desarrolloRESUMEN
The main prerequisite for organism's viability is the maintenance of the internal environment despite changes in the external environment, which is provided by the neuroendocrine control system. The key unit in this system is hypothalamus exerting endocrine effects on certain peripheral organs and anterior pituitary. Physiologically active substances of neuronal origin enter blood vessels in the neurohemal parts of hypothalamus where no blood-brain barrier exists. In other parts of the adult brain, the arrival of physiologically active substances is blocked by the blood-brain barrier. According to the generally accepted concept, the neuroendocrine system formation in ontogeny starts with the maturation of peripheral endocrine glands, which initially function autonomously and then are controlled by the anterior pituitary. The brain is engaged in neuroendocrine control after its maturation completes, which results in a closed control system typical of adult mammals. Since neurons start to secrete physiologically active substances soon after their formation and long before interneuronal connections are formed, these cells are thought to have an effect on brain development as inducers. Considering that there is no blood-brain barrier during this period, we proposed the hypothesis that the developing brain functions as a multipotent endocrine organ. This means that tens of physiologically active substances arrive from the brain to the systemic circulation and have an endocrine effect on the whole body development. Dopamine, serotonin, and gonadotropin-releasing hormone were selected as marker physiologically active substances of cerebral origin to test this hypothesis. In adult animals, they act as neurotransmitters or neuromodulators transmitting information from neuron to neuron as well as neurohormones arriving from the hypothalamus with portal blood to the anterior pituitary. Perinatal rats--before the blood-brain barrier is formed--proved to have equally high concentration of dopamine, serotonin, and gonadotropin-releasing hormone in the systemic circulation as in the adult portal system. After the brain-blood barrier is formed, the blood concentration of dopamine and gonadotropin-releasing hormone drops to zero, which indirectly confirms their cerebral origin. Moreover, the decrease in the blood concentration of dopamine, serotonin, and gonadotropin-releasing hormone before the brain-blood barrier formation after the microsurgical disruption of neurons that synthesize them or inhibition of dopamine and serotonin synthesis in the brain directly confirm their cerebral origin. Before the blood-brain barrier formation, dopamine, serotonin, gonadotropin-releasing hormone, and likely many other physiologically active substances of cerebral origin can have endocrine effects on peripheral target organs--anterior pituitary, gonads, kidney, heart, blood vessels, and the proper brain. Although the period of brain functioning as an endocrine organ is not long, it is crucial for the body development since physiologically active substances exert irreversible effects on the targets as morphogenetic factors during this period. Thus, the developing brain from the neuron formation to the establishment of the blood-brain barrier functions as a multipotent endocrine organ participating in endocrine control of the whole body development.
Asunto(s)
Barrera Hematoencefálica/crecimiento & desarrollo , Encéfalo/crecimiento & desarrollo , Neurogénesis/fisiología , Sistemas Neurosecretores/crecimiento & desarrollo , Animales , Barrera Hematoencefálica/embriología , Barrera Hematoencefálica/fisiología , Encéfalo/embriología , Encéfalo/fisiología , Dopamina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Hipotálamo/embriología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/fisiología , Mamíferos , Neuronas/metabolismo , Sistemas Neurosecretores/embriología , Sistemas Neurosecretores/fisiología , Serotonina/metabolismoRESUMEN
Maternal bioactive substances, such as hormones and neuropeptides, are thought to be essential for fetal development. Recently, ghrelin, a gastrointestinal peptide, has been shown to pass through the rat placenta. The ghrelin receptor, growth hormone secretagogue receptor (GHS-R), has been shown to be expressed in the rat fetal central nervous system, and plasma ghrelin levels are related to birth weight in the rodent and human. In the present study, we report a role of maternal ghrelin in mouse fetal brain development. When ghrelin was administrated to pregnant mice, pups exhibited suppression of exploratory behavior in an open-field (OF) test. Control pups, however, remained for longer periods of time in the center area, correlating with exploratory behavior. Basal corticotropin-releasing hormone (CRH) plasma levels were greater in pups from ghrelin-treated dams, and did not change in response to acute restraint stress. Moreover, reduced growth hormone secretagogue receptor and neuropeptide Y mRNA expression was observed in the hypothalamus at postnatal day 3 and remained until 16 weeks of age. In addition, under physiological condition, increased maternal ghrelin plasma levels following repeated restraint stress to the dam had effect on the increase in fetal plasma acyl ghrelin levels. These results suggest that maternal ghrelin affect fetal plasma ghrelin levels and alters endocrine systems and behaviors of offspring.
Asunto(s)
Conducta Animal/fisiología , Ghrelina/sangre , Sistema Hipotálamo-Hipofisario/metabolismo , Sistemas Neurosecretores/metabolismo , Hormonas Adenohipofisarias/metabolismo , Estrés Psicológico/metabolismo , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Hormona Liberadora de Corticotropina/metabolismo , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Femenino , Ghrelina/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Intercambio Materno-Fetal/fisiología , Ratones , Ratones Endogámicos C57BL , Neuropéptido Y/genética , Sistemas Neurosecretores/efectos de los fármacos , Sistemas Neurosecretores/crecimiento & desarrollo , Embarazo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Somatotropina/efectos de los fármacos , Receptores de Somatotropina/metabolismo , Restricción Física/fisiología , Estrés Psicológico/fisiopatologíaRESUMEN
Endocrine disrupting chemicals (EDCs) are natural or synthetic compounds that interfere with the normal function of an organism's endocrine system. Many EDCs are resistant to biodegradation, due to their structural stability, and persist in the environment. The focus of this review is on natural and artificial EDCs that act through estrogenic mechanisms to affect reproductive neuroendocrine systems. This endocrine axis comprises the hypothalamic gonadotropin-releasing hormone (GnRH), pituitary gonadotropins, and gonadal steroid hormones, including estrogens. Although it is not surprising that EDCs that mimic or antagonize estrogen receptors may exert actions upon reproductive targets, the mechanisms for these effects are complex and involve all three levels of the hypothalamic-pituitary-gonadal (HPG) system. Nevertheless, considerable evidence links exposure to estrogenic environmental EDCs with neuroendocrine reproductive deficits in wildlife and in humans. The effects of an EDC are variable across the life cycle of an animal, and are particularly potent when exposure occurs during fetal and early postnatal development. As a consequence, abnormal sexual differentiation, disrupted reproductive function, or inappropriate sexual behavior may be detected later in life. This review will cover the effects of two representative classes of estrogenic EDCs, phytoestrogens and polychlorinated biphenyls (PCBs), on neuroendocrine reproductive function, from molecules to behavior, across the vertebrate life cycle. Finally, we identify the gaps of knowledge in this field and suggest future directions for study.
Asunto(s)
Disruptores Endocrinos/toxicidad , Sistema Endocrino/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Sistemas Neurosecretores/efectos de los fármacos , Animales , Sistema Endocrino/crecimiento & desarrollo , Sistema Endocrino/metabolismo , Femenino , Masculino , Sistemas Neurosecretores/crecimiento & desarrollo , Sistemas Neurosecretores/metabolismo , Fitoestrógenos/toxicidad , Bifenilos Policlorados/toxicidad , Maduración Sexual/efectos de los fármacosRESUMEN
Thyroid hormones play an important role in brain development. In the present study, we examined the influence of transient postnatal hypothyroidism on reproductive neuroendocrine and behavioral outcomes in the male Syrian (golden) hamster. Hamster pups were rendered hypothyroid following exposure to the goitrogen, 6-n-propyl-2-thiouracil (PTU), between postnatal (PN) day 0 (birth) and PN25 (weaning). By 15 days after cessation of PTU, exposure (PN40) serum thyroxine levels had returned to control levels. The testes of treated males were approximately 30% heavier than controls and daily sperm production was increased by 73%. Immunocytochemistry for GnRH revealed that the total number of GnRH neurons did not vary between groups; however, a shift in the distribution of GnRH neurons was observed in treated males such that more GnRH immunoreactive neurons were found in the caudal portion of their normal distribution. The shift in GnRH distribution was associated with a significant reduction (40-50%) in pituitary gonadotropin secretion. Behaviorally, treated males took significantly longer to investigate the anogenital region and then mount a receptive female. A corresponding reduction in the total number of anogenital investigations and mounts was observed. This difference between treated males and controls was reduced, but not eliminated, over successive trials and by the third trial the number of intromission was similar between treated and control males. We conclude that the full complement of adult reproductive functions observed in the male golden hamster requires thyroid hormones during the early postnatal period. The severity of the effects induced by early hypothyroidism in this species varies from transient to permanent, depending on the endpoint.