RESUMO
BACKGROUND: Estrogen secretion by the ovaries regulates the hypothalamic-pituitary-gonadal axis during the reproductive cycle, influencing gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion, and also plays a role in regulating metabolism. Here, we establish that hypothalamic tanycytes-specialized glia lining the floor and walls of the third ventricle-integrate estrogenic feedback signals from the gonads and couple reproduction with metabolism by relaying this information to orexigenic neuropeptide Y (NPY) neurons. METHODS: Using mouse models, including mice floxed for Esr1 (encoding estrogen receptor alpha, ERα) and those with Cre-dependent expression of designer receptors exclusively activated by designer drugs (DREADDs), along with viral-mediated, pharmacological and indirect calorimetric approaches, we evaluated the role of tanycytes and tanycytic estrogen signaling in pulsatile LH secretion, cFos expression in NPY neurons, estrous cyclicity, body-weight changes and metabolic parameters in adult females. RESULTS: In ovariectomized mice, chemogenetic activation of tanycytes significantly reduced LH pulsatile release, mimicking the effects of direct NPY neuron activation. In intact mice, tanycytes were crucial for the estrogen-mediated control of GnRH/LH release, with tanycytic ERα activation suppressing fasting-induced NPY neuron activation. Selective knockout of Esr1 in tanycytes altered estrous cyclicity and fertility in female mice and affected estrogen's ability to inhibit refeeding in fasting mice. The absence of ERα signaling in tanycytes increased Npy transcripts and body weight in intact mice and prevented the estrogen-mediated decrease in food intake as well as increase in energy expenditure and fatty acid oxidation in ovariectomized mice. CONCLUSIONS: Our findings underscore the pivotal role of tanycytes in the neuroendocrine coupling of reproduction and metabolism, with potential implications for its age-related deregulation after menopause. SIGNIFICANCE STATEMENT: Our investigation reveals that tanycytes, specialized glial cells in the brain, are key interpreters of estrogen signals for orexigenic NPY neurons in the hypothalamus. Disrupting tanycytic estrogen receptors not only alters fertility in female mice but also impairs the ability of estrogens to suppress appetite. This work thus sheds light on the critical role played by tanycytes in bridging the hormonal regulation of cyclic reproductive function and appetite/feeding behavior. This understanding may have potential implications for age-related metabolic deregulation after menopause.
Assuntos
Células Ependimogliais , Receptor alfa de Estrogênio , Fertilidade , Hormônio Luteinizante , Transdução de Sinais , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Camundongos , Fertilidade/fisiologia , Células Ependimogliais/metabolismo , Transdução de Sinais/fisiologia , Hormônio Luteinizante/metabolismo , Ciclo Estral/fisiologia , Ciclo Estral/metabolismo , Neuropeptídeo Y/metabolismo , Ovariectomia , Neurônios/metabolismo , Hipotálamo/metabolismo , Camundongos Endogâmicos C57BL , Hormônio Liberador de Gonadotropina/metabolismoRESUMO
INTRODUCTION: In humans, prenatal androgen excess can lead to a broad spectrum of pathologies in adulthood, including polycystic ovary syndrome (PCOS). Women with PCOS present a variety of reproductive and metabolic disturbances and they also face increased risk to develop neuropsychiatric disorders such as depression and anxiety. Despite the high prevalence, the cause of depressive and anxiety symptoms is not fully elucidated. The use of androgenized ewe models can provide valuable insights into the pathogenesis of PCOS, as they closely mimic the reproductive, neuroendocrine, and metabolic characteristics observed in women with this condition. METHOD: We studied the impact of prenatal exposure to testosterone propionate on cognitive and behavioral performances of Ile-de-France ewes, using a plethora of behavioral tests for anxiety and cognitive performances. RESULTS: Our findings indicate that prenatal androgenized ewes exhibit markedly elevated levels of anxiety-like behavior compared to control animals, while showing no discernible differences in cognitive performance. CONCLUSION: These discoveries offer novel perspectives on how maternal androgen excess contributes to anxiogenic effects in PCOS preclinical models, underscoring the ewe's significance as a model for conducting mechanistic studies to unravel the physiological and molecular aspects of anxiety.
Assuntos
Ansiedade , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Gravidez , Ansiedade/induzido quimicamente , Ovinos , Propionato de Testosterona/farmacologia , Propionato de Testosterona/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Androgênios/farmacologia , Androgênios/efeitos adversos , Modelos Animais de Doenças , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/metabolismo , Cognição/efeitos dos fármacosRESUMO
Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.
Le syndrome des ovaires polykystiques (SOPK) est le trouble endocrinien et métabolique le plus répandu chez les femmes en âge de procréer, avec une forte composante héréditaire estimée entre 60 et 70%. Les facteurs environnementaux pendant la période fÅtale pourraient être impliqués dans l'apparition du syndrome à l'âge adulte. Néanmoins, les mécanismes sous-jacents à sa transmission demeurent inconnus, limitant ainsi le développement de thérapies efficaces.Cet article met en lumière comment un environnement fÅtal altéré (exposition prénatale à des taux élevés d'hormone anti-müllerienne) pourrait contribuer à la survenue du SOPK chez la descendance ainsi qu'à la transmission transgénérationnelle des caractéristiques neuroendocriniennes et métaboliques du SOPK, par le biais d'une altération du processus de la méthylation de l'ADN.L'originalité des travaux translationnels présentés ici repose d'une part sur l'identification de potentiels biomarqueurs de diagnostic précoce du syndrome. Et d'autre part, sur la validation d'une piste thérapeutique prometteuse dans un modèle préclinique de SOPK, offrant ainsi des perspectives d'amélioration de la prise en charge des patientes atteintes de ce syndrome.
Assuntos
Síndrome do Ovário Policístico , Gravidez , Feminino , Humanos , Síndrome do Ovário Policístico/etiologia , Síndrome do Ovário Policístico/genética , Fenótipo , Hormônio Antimülleriano , ReproduçãoRESUMO
In recent years, the expanding roles of anti-Müllerian hormone (AMH) in various aspects of reproductive health have attracted significant attention. Initially recognized for its classical role in male sexual differentiation, AMH is produced postnatally by the Sertoli cells in the male testes and by the granulosa cells in the female ovaries. Traditionally, it was believed to primarily influence gonadal development and function. However, research over the last decade has unveiled novel actions of AMH beyond the gonads, specifically all along the hypothalamic-pituitary-gonadal axis. This review will focus on the emerging roles of AMH within the hypothalamus and discusses its potential implications in reproductive physiology. Additionally, recent preclinical and clinical studies have suggested that elevated levels of AMH may disrupt the hypothalamic network regulating reproduction, which could contribute to the central pathophysiology of polycystic ovary syndrome. These findings underscore the intricate interplay between AMH and the neuroendocrine system, offering new avenues for understanding the mechanisms underlying fertility and reproductive disorders.
Assuntos
Hormônio Antimülleriano , Fertilidade , Hipotálamo , Hormônio Antimülleriano/metabolismo , Humanos , Fertilidade/fisiologia , Feminino , Animais , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Masculino , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/fisiopatologia , Sistema Hipotálamo-Hipofisário/metabolismo , Ovário/metabolismo , Ovário/fisiologia , Transdução de SinaisRESUMO
Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development.
Assuntos
Encéfalo , Microglia , Axônios , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Macrófagos/fisiologia , Microglia/patologia , MorfogêneseRESUMO
BACKGROUND: Triple-Negative Breast Cancer is particularly aggressive, and its metastasis to the brain has a significant psychological impact on patients' quality of life, in addition to reducing survival. The development of brain metastases is particularly harmful in triple-negative breast cancer (TNBC). To date, the mechanisms that induce brain metastasis in TNBC are poorly understood. METHODS: Using a human blood-brain barrier (BBB) in vitro model, an in vitro 3D organotypic extracellular matrix, an ex vivo mouse brain slices co-culture and in an in vivo xenograft experiment, key step of brain metastasis were recapitulated to study TNBC behaviors. RESULTS: In this study, we demonstrated for the first time the involvement of the precursor of Nerve Growth Factor (proNGF) in the development of brain metastasis. More importantly, our results showed that proNGF acts through TrkA independent of its phosphorylation to induce brain metastasis in TNBC. In addition, we found that proNGF induces BBB transmigration through the TrkA/EphA2 signaling complex. More importantly, our results showed that combinatorial inhibition of TrkA and EphA2 decreased TBNC brain metastasis in a preclinical model. CONCLUSIONS: These disruptive findings provide new insights into the mechanisms underlying brain metastasis with proNGF as a driver of brain metastasis of TNBC and identify TrkA/EphA2 complex as a potential therapeutic target.
RESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments. METHODS: We used adult Gnrh1cre female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48 h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations. FINDINGS: We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals. INTERPRETATION: Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS. FUNDING: European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n⦠725149).
Assuntos
Síndrome do Ovário Policístico , Humanos , Feminino , Camundongos , Animais , Hormônio Luteinizante , Hormônio Liberador de Gonadotropina , NeurôniosRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine disorder affecting between 5 and 18% of women worldwide. An elevated frequency of pulsatile luteinizing hormone (LH) secretion and higher serum levels of anti-Müllerian hormone (AMH) are frequently observed in women with PCOS. The origin of these abnormalities is, however, not well understood. METHODS: We studied brain structure and function in women with and without PCOS using proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging combined with fiber tractography. Then, using a mouse model of PCOS, we investigated by electron microscopy whether AMH played a role on the regulation of hypothalamic structural plasticity. FINDINGS: Increased AMH serum levels are associated with increased hypothalamic activity/axonal-glial signalling in PCOS patients. Furthermore, we demonstrate that AMH promotes profound micro-structural changes in the murine hypothalamic median eminence (ME), creating a permissive environment for GnRH secretion. These include the retraction of the processes of specialized AMH-sensitive ependymo-glial cells called tanycytes, allowing more GnRH neuron terminals to approach ME blood capillaries both during the run-up to ovulation and in a mouse model of PCOS. INTERPRETATION: We uncovered a central function for AMH in the regulation of fertility by remodeling GnRH terminals and their tanycytic sheaths, and provided insights into the pivotal role of the brain in the establishment and maintenance of neuroendocrine dysfunction in PCOS. FUNDING: INSERM (U1172), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n° 725149), CHU de Lille, France (Bonus H).
Assuntos
Síndrome do Ovário Policístico , Humanos , Animais , Camundongos , Feminino , Hormônio Luteinizante , Hormônio Antimülleriano , Imagem de Tensor de Difusão , Hormônio Liberador de Gonadotropina , Neuroglia/patologiaRESUMO
In vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome are rare genetic disorders characterized by infertility, and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling. Here, we documented the expression of the jagged-1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knockdown of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs. Next-generation sequencing was performed in 467 CHH unrelated probands, leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibited reduced protein levels and altered subcellular localization. Together our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons, and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans.
Assuntos
Hormônio Liberador de Gonadotropina , Hipogonadismo , Feminino , Gravidez , Animais , Humanos , Hormônio Liberador de Gonadotropina/genética , Proteína Jagged-1/genética , Peixe-Zebra , Transdução de Sinais , Hipogonadismo/genéticaRESUMO
The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1. The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.
Assuntos
Hipogonadismo , Óxido Nítrico , Animais , Cognição , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Hipogonadismo/complicações , Hipogonadismo/congênito , Hipogonadismo/genética , Camundongos , Proteínas Mutantes , Mutação/genética , Óxido Nítrico Sintase Tipo I/genética , NitritosRESUMO
Hypothalamic gonadotropin-releasing hormone (GnRH) neurons lay the foundation for human development and reproduction; however, the critical cell populations and the entangled mechanisms underlying the development of human GnRH neurons remain poorly understood. Here, by using our established human pluripotent stem cell-derived GnRH neuron model, we decoded the cellular heterogeneity and differentiation trajectories at the single-cell level. We found that a glutamatergic neuron population, which generated together with GnRH neurons, showed similar transcriptomic properties with olfactory sensory neuron and provided the migratory path for GnRH neurons. Through trajectory analysis, we identified a specific gene module activated along the GnRH neuron differentiation lineage, and we examined one of the transcription factors, DLX5, expression in human fetal GnRH neurons. Furthermore, we found that Wnt inhibition could increase DLX5 expression and improve the GnRH neuron differentiation efficiency through promoting neurogenesis and switching the differentiation fates of neural progenitors into glutamatergic neurons/GnRH neurons. Our research comprehensively reveals the dynamic cell population transition and gene regulatory network during GnRH neuron differentiation.
Assuntos
Hormônio Liberador de Gonadotropina , Células-Tronco Pluripotentes , Humanos , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Via de Sinalização Wnt/genética , Neurônios/metabolismo , Diferenciação Celular/genética , Células-Tronco Pluripotentes/metabolismoRESUMO
Gonadotropin-releasing hormone isoform I (GnRH), a neuro-deca-peptide, plays a fundamental role in development and maintenance of the reproductive system in vertebrates. The anomalous release of GnRH is observed in reproductive disorder such as hypogonadotropic hypogonadism, polycystic ovary syndrome (PCOS), or following prenatal exposure to elevated androgen levels. Quantitation of GnRH plasma levels could help to diagnose and better understand these pathologies. Here, a validated nano-high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) method to quantify GnRH in ewe plasma samples is presented. Protein precipitation and solid-phase extraction (SPE) pre-treatment steps were required to purify and enrich GnRH and internal standard (lamprey-luteinizing hormone-releasing hormone-III, l-LHRH-III). For the validation process, a surrogate matrix approach was chosen following the International Council for Harmonisation (ICH) and FDA guidelines. Before the validation study, the validation model using the surrogate matrix was compared with those using a real matrix such as human plasma. All the tested parameters were analogous confirming the use of the surrogate matrix as a standard calibration medium. From the validation study, limit of detection (LOD) and limit of quantitation (LOQ) values of 0.008 and 0.024 ng/mL were obtained, respectively. Selectivity, accuracy, precision, recovery, and matrix effect were assessed with quality control samples in human plasma and all values were acceptable. Sixteen samples belonging to healthy and prenatal androgen (PNA) exposed ewes were collected and analyzed, and the GnRH levels ranged between 0.05 and 3.26 ng/mL. The nano-HPLC-HRMS developed here was successful in measuring GnRH, representing therefore a suitable technique to quantify GnRH in ewe plasma and to detect it in other matrices and species.
Assuntos
Androgênios , Hormônio Liberador de Gonadotropina , Gravidez , Ovinos , Feminino , Animais , Humanos , Projetos Piloto , Hormônio Liberador de Gonadotropina/metabolismo , Cromatografia Líquida de Alta Pressão , Isoformas de ProteínasRESUMO
At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.
Assuntos
Cognição , Disfunção Cognitiva , Síndrome de Down , Hormônio Liberador de Gonadotropina , Transtornos do Olfato , Adulto , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Síndrome de Down/complicações , Síndrome de Down/tratamento farmacológico , Síndrome de Down/psicologia , Feminino , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Liberador de Gonadotropina/fisiologia , Hormônio Liberador de Gonadotropina/uso terapêutico , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Transtornos do Olfato/tratamento farmacológico , Transtornos do Olfato/etiologia , Transmissão Sináptica/efeitos dos fármacos , Adulto JovemRESUMO
Women with polycystic ovary syndrome (PCOS) frequently experience decreased sexual arousal, desire, and sexual satisfaction. While the hypothalamus is known to regulate sexual behavior, the specific neuronal pathways affected in patients with PCOS are not known. To dissect the underlying neural circuitry, we capitalized on a robust preclinical animal model that reliably recapitulates all cardinal PCOS features. We discovered that female mice prenatally treated with anti-Müllerian hormone (PAMH) display impaired sexual behavior and sexual partner preference over the reproductive age. Blunted female sexual behavior was associated with increased sexual rejection and independent of sex steroid hormone status. Structurally, sexual dysfunction was associated with a substantial loss of neuronal nitric oxide synthase (nNOS)-expressing neurons in the ventromedial nucleus of the hypothalamus (VMH) and other areas of hypothalamic nuclei involved in social behaviors. Using in vivo chemogenetic manipulation, we show that nNOSVMH neurons are required for the display of normal sexual behavior in female mice and that pharmacological replenishment of nitric oxide restores normal sexual performance in PAMH mice. Our data provide a framework to investigate facets of hypothalamic nNOS neuron biology with implications for sexual disturbances in PCOS.
Assuntos
Óxido Nítrico Sintase Tipo I , Óxido Nítrico , Síndrome do Ovário Policístico , Comportamento Sexual , Núcleo Hipotalâmico Ventromedial , Animais , Hormônio Antimülleriano/farmacologia , Modelos Animais de Doenças , Feminino , Preferência de Acasalamento Animal , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Síndrome do Ovário Policístico/enzimologia , Síndrome do Ovário Policístico/fisiopatologia , Núcleo Hipotalâmico Ventromedial/efeitos dos fármacos , Núcleo Hipotalâmico Ventromedial/metabolismoRESUMO
p140Cap, encoded by the gene SRCIN1 (SRC kinase signaling inhibitor 1), is an adaptor/scaffold protein highly expressed in the mouse brain, participating in several pre- and post-synaptic mechanisms. p140Cap knock-out (KO) female mice show severe hypofertility, delayed puberty onset, altered estrus cycle, reduced ovulation, and defective production of luteinizing hormone and estradiol during proestrus. We investigated the role of p140Cap in the development and maturation of the hypothalamic gonadotropic system. During embryonic development, migration of Gonadotropin-Releasing Hormone (GnRH) neurons from the nasal placode to the forebrain in p140Cap KO mice appeared normal, and young p140Cap KO animals showed a normal number of GnRH-immunoreactive (-ir) neurons. In contrast, adult p140Cap KO mice showed a significant loss of GnRH-ir neurons and a decreased density of GnRH-ir projections in the median eminence, accompanied by reduced levels of GnRH and LH mRNAs in the hypothalamus and pituitary gland, respectively. We examined the number of kisspeptin (KP) neurons in the rostral periventricular region of the third ventricle, the number of KP-ir fibers in the arcuate nucleus, and the number of KP-ir punctae on GnRH neurons but we found no significant changes. Consistently, the responsiveness to exogenous KP in vivo was unchanged, excluding a cell-autonomous defect on the GnRH neurons at the level of KP receptor or its signal transduction. Since glutamatergic signaling in the hypothalamus is critical for both puberty onset and modulation of GnRH secretion, we examined the density of glutamatergic synapses in p140Cap KO mice and observed a significant reduction in the density of VGLUT-ir punctae both in the preoptic area and on GnRH neurons. Our data suggest that the glutamatergic circuitry in the hypothalamus is altered in the absence of p140Cap and is required for female fertility.
RESUMO
This review summarizes the current understanding of the development of the neuroendocrine gonadotropin-releasing hormone (GnRH) system, including discussion on open questions regarding (1) transcriptional regulation of the Gnrh1 gene; (2) prenatal development of the GnRH1 system in rodents and humans; and (3) paracrine and synaptic communication during migration of the GnRH cells.
Assuntos
Hormônio Liberador de Gonadotropina , Neurônios , Feminino , Regulação da Expressão Gênica , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Neurônios/metabolismo , Sistemas Neurossecretores/metabolismo , GravidezRESUMO
The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.
Assuntos
Movimento Celular , Rastreamento de Células , Células/citologia , Biologia do Desenvolvimento/métodos , Embrião de Mamíferos/citologia , Feto/citologia , Disseminação de Informação , Organogênese , Adulto , Animais , Atlas como Assunto , Técnicas de Cultura de Células , Sobrevivência Celular , Visualização de Dados , Feminino , Humanos , Imageamento Tridimensional , Masculino , Modelos Animais , Organogênese/genética , Organoides/citologia , Células-Tronco/citologiaRESUMO
Here, we describe a protocol that provides the steps required for the generation of a mouse model of polycystic ovary syndrome (PCOS) by exposing dams to elevated levels of anti-Müllerian hormone during late gestation. This protocol also describes the steps required to assess the PCOS-like equivalents of the Rotterdam PCOS diagnostic criteria in mice. For complete details on the use and execution of this protocol, please refer to Tata et al. (2018) and Mimouni et al. (2021).
Assuntos
Hormônio Antimülleriano/efeitos adversos , Modelos Animais de Doenças , Síndrome do Ovário Policístico/fisiopatologia , Animais , Feminino , Camundongos , Hormônios Peptídicos/efeitos adversos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologiaRESUMO
Human reproduction is controlled by ~2000 hypothalamic gonadotropin-releasing hormone (GnRH) neurons. Here, we report the discovery and characterization of additional ~150,000-200,000 GnRH-synthesizing cells in the human basal ganglia and basal forebrain. Nearly all extrahypothalamic GnRH neurons expressed the cholinergic marker enzyme choline acetyltransferase. Similarly, hypothalamic GnRH neurons were also cholinergic both in embryonic and adult human brains. Whole-transcriptome analysis of cholinergic interneurons and medium spiny projection neurons laser-microdissected from the human putamen showed selective expression of GNRH1 and GNRHR1 autoreceptors in the cholinergic cell population and uncovered the detailed transcriptome profile and molecular connectome of these two cell types. Higher-order non-reproductive functions regulated by GnRH under physiological conditions in the human basal ganglia and basal forebrain require clarification. The role and changes of GnRH/GnRHR1 signaling in neurodegenerative disorders affecting cholinergic neurocircuitries, including Parkinson's and Alzheimer's diseases, need to be explored.
Assuntos
Gânglios da Base , Hormônio Liberador de Gonadotropina/metabolismo , Neurônios , Adulto , Prosencéfalo Basal/citologia , Gânglios da Base/citologia , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Células Cultivadas , Colina O-Acetiltransferase , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/citologia , Neurônios/metabolismo , Neurônios/fisiologia , Putamen/citologia , TranscriptomaRESUMO
The survival of the species depends on two closely interlinked processes: the correct functioning of the reproductive system, and the balance between the energy needs of an individual and the supply of energy sources through feeding. These two processes are regulated in the hypothalamus, which produces neurohormones that control various physiological functions. Among these neurohormones, GnRH controls not only the maturation and function of the reproductive organs, including the ovaries and the testes, during puberty and in adulthood, but also sexual attraction. Recent evidence suggest that neuropilin-1-mediated signaling in GnRH-synthesizing neurons could be a linchpin that holds together various neuroanatomical, physiological and behavioral adaptations involved in triggering puberty and achieving reproductive function.
TITLE: Signalisation impliquant la neuropiline dans les neurones sécrétant la GnRH - Son rôle dans le déclenchement de la puberté. ABSTRACT: La survie d'une espèce dépend de deux processus intimement liés : la reproduction, d'une part, et l'équilibre entre les besoins énergétiques et l'approvisionnement en sources d'énergie par l'alimentation, d'autre part. Ces deux processus sont contrôlés dans le cerveau par l'hypothalamus, qui produit des neurohormones agissant sur l'hypophyse pour piloter diverses fonctions physiologiques. L'une de ces neurohormones, la GnRH, contrôle non seulement la maturation et le fonctionnement des organes reproducteurs, incluant les ovaires et les testicules, lors de la puberté et à l'âge adulte, mais aussi l'attirance sexuelle. De récentes découvertes suggèrent que la signalisation impliquant la neuropiline-1 dans les neurones sécrétant la GnRH jouerait un rôle charnière dans la coordination du neurodéveloppement et des adaptations physiologiques et comportementales nécessaires au déclenchement de la puberté et à l'acquisition de la fonction de reproduction. Dans cet article de synthèse, nous replaçons ces découvertes dans le contexte de récents travaux montrant que les voies de signalisation des sémaphorines de classe 3 sont impliquées dans la physiopathologie non seulement de l'infertilité, mais aussi de l'obésité. Nous discutons également l'implication potentielle des neurones produisant la GnRH dans la perception des odeurs sociales et dans la précocité de la maturation sexuelle. L'hypothèse selon laquelle l'activité de ces neurones au cours du développement postnatal constituerait le chaînon manquant entre la prise de poids, le déclenchement de la puberté et le comportement sexuel, ouvre la voie à une meilleure compréhension de l'implication de l'homéostasie énergétique dans la maturation sexuelle, et pourrait aussi avoir des implications thérapeutiques pour la puberté précoce.