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1.
World Neurosurg ; 184: 125, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38219802

RESUMEN

Isolated unilateral hydrocephalus (IUH) is a condition caused by unilateral obstruction of the foramen of Monro.1 Etiopathogenic causes include tumors, congenital lesions, infective ventriculitis, intraventricular haemorrhage, and iatrogenic causes such as the presence of contralateral shunts.2,3 Neuroendoscopic management is considered the "gold-standard" treatment in IUH.4 Even if endoscopic septostomy and foraminoplasty in IUH are well-known procedures,5,6 IUH after an interhemispheric transcallosal transchoroidal approach for removal of a III ventricle colloid cyst is a complication barely described in literature. Video 1 describes this rare complication and the neuroendoscopic treatment adopted, including the operative room setup, patient's positioning, instrumentation needed, and a series of intraoperative tips for the performance of septostomy and Monroplasty via a single, precoronal burr hole. The scalp entry point and endoscope trajectory, homolateral to the dilated ventricle, were planned on the neuronavigation system. The avascular septal zone away from the septal veins and body of the fornix was reached, and the ostomy was performed. At the end of the procedure, Monroplasty was performed, too. The procedure was effective in solving the hydrocephalus and patient's clinical picture. No surgical complications occurred. Imaging demonstrated an evident and progressive reduction of enlarged lateral ventricle. In authors' opinion, the single burr-hole approach, ipsilateral to the enlarged ventricle, provides an optimal identification the intraventricular anatomy and allows Monroplasty to be performed, if deemed feasible during surgery. The patient consented to the procedure. The participants and any identifiable individuals consented to publication of their images.


Asunto(s)
Quiste Coloide , Hidrocefalia , Neuroendoscopía , Tercer Ventrículo , Humanos , Ventrículos Laterales , Tercer Ventrículo/cirugía , Quiste Coloide/diagnóstico por imagen , Quiste Coloide/cirugía , Quiste Coloide/complicaciones , Ventrículos Cerebrales/cirugía , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/etiología , Hidrocefalia/cirugía , Neuroendoscopía/métodos
2.
Sci Transl Med ; 14(665): eabh2369, 2022 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-36197968

RESUMEN

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.


Asunto(s)
Hipogonadismo , Óxido Nítrico , Animales , Cognición , Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Humanos , Hipogonadismo/complicaciones , Hipogonadismo/congénito , Hipogonadismo/genética , Ratones , Proteínas Mutantes , Mutación/genética , Óxido Nítrico Sintasa de Tipo I/genética , Nitritos
3.
Science ; 377(6610): eabq4515, 2022 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-36048943

RESUMEN

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.


Asunto(s)
Cognición , Disfunción Cognitiva , Síndrome de Down , Hormona Liberadora de Gonadotropina , Trastornos del Olfato , Adulto , Animales , Cognición/efectos de los fármacos , Cognición/fisiología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Modelos Animales de Enfermedad , Síndrome de Down/complicaciones , Síndrome de Down/tratamiento farmacológico , Síndrome de Down/psicología , Femenino , Hormona Liberadora de Gonadotropina/farmacología , Hormona Liberadora de Gonadotropina/fisiología , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Trastornos del Olfato/tratamiento farmacológico , Trastornos del Olfato/etiología , Transmisión Sináptica/efectos de los fármacos , Adulto Joven
4.
Proc Natl Acad Sci U S A ; 119(27): e2113749119, 2022 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-35763574

RESUMEN

Kisspeptin neurons in the mediobasal hypothalamus (MBH) are critical targets of ovarian estrogen feedback regulating mammalian fertility. To reveal molecular mechanisms underlying this signaling, we thoroughly characterized the estrogen-regulated transcriptome of kisspeptin cells from ovariectomized transgenic mice substituted with 17ß-estradiol or vehicle. MBH kisspeptin neurons were harvested using laser-capture microdissection, pooled, and subjected to RNA sequencing. Estrogen treatment significantly (p.adj. < 0.05) up-regulated 1,190 and down-regulated 1,139 transcripts, including transcription factors, neuropeptides, ribosomal and mitochondrial proteins, ion channels, transporters, receptors, and regulatory RNAs. Reduced expression of the excitatory serotonin receptor-4 transcript (Htr4) diminished kisspeptin neuron responsiveness to serotonergic stimulation. Many estrogen-regulated transcripts have been implicated in puberty/fertility disorders. Patients (n = 337) with congenital hypogonadotropic hypogonadism (CHH) showed enrichment of rare variants in putative CHH-candidate genes (e.g., LRP1B, CACNA1G, FNDC3A). Comprehensive characterization of the estrogen-dependent kisspeptin neuron transcriptome sheds light on the molecular mechanisms of ovary-brain communication and informs genetic research on human fertility disorders.


Asunto(s)
Núcleo Arqueado del Hipotálamo , Estrógenos , Fertilidad , Kisspeptinas , Neuronas , Ovario , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Estrógenos/metabolismo , Femenino , Fertilidad/genética , Perfilación de la Expresión Génica , Humanos , Hipogonadismo/congénito , Hipogonadismo/genética , Kisspeptinas/genética , Kisspeptinas/metabolismo , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Ovario/metabolismo
5.
Phys Med ; 94: 75-84, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34999515

RESUMEN

PURPOSE: One of the obstacles to the application of Boron Neutron Capture Therapy (BNCT) and Proton Boron Fusion Therapy (PBFT) concerns the measurement of borated carriers' biodistribution. The objective of the present study was to evaluate the in vitro internalization of the 19F-labelled p-boronophenylalanine (19F-BPA) in the human cancer pancreatic cell line (PANC-1) for the potential application of BNCT and PBFT in pancreatic cancer. The 19F-BPA carrier has the advantage that its bio-distribution may be monitored in vivo using 19F-Nuclear Magnetic Resonance (19F NMR). MATERIALS AND METHODS: The 19F-BPA internalization in PANC-1 cells was evaluated using three independent techniques on cellular samples left in contact with growing medium enriched with 13.6 mM 19F-BPA corresponding to a 11B concentration of 120 ppm: neutron autoradiography, which quantifies boron; liquid chromatography hyphenated to tandem mass spectrometry and UV-Diode Array Detection (UV-DAD), which quantifies 19F-BPA molecule; and 19F NMR spectroscopy, which detects fluorine nuclei. RESULTS: Our studies suggested that 19F-BPA is internalized by PANC-1 cells. The three methods provided consistent results of about 50% internalization fraction at 120 ppm of 11B. Small variations (less than 15%) in internalization fraction are mainly dependent on the proliferation state of the cells. CONCLUSIONS: The ability of 19F NMR spectroscopy to study 19F-BPA internalization was validated by well-established independent techniques. The multimodal approach we used suggests 19F-BPA as a promising BNCT/PBFT carrier for the treatment of pancreatic cancer. Since the quantification is performed at doses useful for BNCT/PBFT, 19F NMR can be envisaged to monitor 19F-BPA bio-distribution during the therapy.


Asunto(s)
Terapia por Captura de Neutrón de Boro , Neoplasias Pancreáticas , Terapia de Protones , Boro , Compuestos de Boro , Humanos , Neoplasias Pancreáticas/radioterapia , Distribución Tisular
6.
Artículo en Inglés | MEDLINE | ID: mdl-34152287

RESUMEN

SUMMARY: Complete androgen-insensitivity syndrome (CAIS), a disorder of sex development (46,XY DSD), is caused primarily by mutations in the androgen receptor (AR). Gonadectomy is recommended due to the increased risk of gonadoblastoma, however, surgical intervention is often followed by loss of libido. We present a 26-year-old patient with CAIS who underwent gonadectomy followed by a significant decrease in libido, which was improved with testosterone treatment but not with estradiol. Genetic testing was performed and followed by molecular characterization. We found that this patient carried a previously unidentified start loss mutation in the androgen receptor. This variant resulted in an N-terminal truncated protein with an intact DNA binding domain and was confirmed to be loss-of-function in vitro. This unique CAIS case and detailed functional studies raise intriguing questions regarding the relative roles of testosterone and estrogen in libido, and in particular, the potential non-genomic actions of androgens. LEARNING POINTS: N-terminal truncation of androgen receptor can cause androgen-insensitivity syndrome. Surgical removal of testosterone-producing gonads can result in loss of libido. Libido may be improved with testosterone treatment but not with estradiol in some forms of CAIS. A previously unreported AR mutation - p.Glu2_Met190del (c.2T>C) - is found in a CAIS patient and results in blunted AR transcriptional activity under testosterone treatment.

7.
EMBO J ; 39(19): e104633, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32761635

RESUMEN

Hypothalamic neurons expressing gonadotropin-releasing hormone (GnRH), the "master molecule" regulating reproduction and fertility, migrate from their birthplace in the nose to their destination using a system of guidance cues, which include the semaphorins and their receptors, the neuropilins and plexins, among others. Here, we show that selectively deleting neuropilin-1 in new GnRH neurons enhances their survival and migration, resulting in excess neurons in the hypothalamus and in their unusual accumulation in the accessory olfactory bulb, as well as an acceleration of mature patterns of activity. In female mice, these alterations result in early prepubertal weight gain, premature attraction to male odors, and precocious puberty. Our findings suggest that rather than being influenced by peripheral energy state, GnRH neurons themselves, through neuropilin-semaphorin signaling, might engineer the timing of puberty by regulating peripheral adiposity and behavioral switches, thus acting as a bridge between the reproductive and metabolic axes.


Asunto(s)
Regulación de la Expresión Génica , Hormona Liberadora de Gonadotropina/metabolismo , Neuronas/metabolismo , Neuropilina-1/biosíntesis , Conducta Sexual Animal , Maduración Sexual , Aumento de Peso , Animales , Femenino , Hormona Liberadora de Gonadotropina/genética , Masculino , Ratones , Ratones Transgénicos , Neuropilina-1/genética
8.
Elife ; 82019 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-31291191

RESUMEN

Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of CHH probands using whole-exome sequencing. We showed that during embryonic development, AMH is expressed in migratory GnRH neurons in both mouse and human fetuses and unconvered a novel function of AMH as a pro-motility factor for GnRH neurons. Pathohistological analysis of Amhr2-deficient mice showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in reduced fertility in adults. Our findings highlight a novel role for AMH in the development and function of GnRH neurons and indicate that AMH signaling insufficiency contributes to the pathogenesis of CHH in humans.


Asunto(s)
Hormona Antimülleriana/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hipogonadismo/metabolismo , Neuronas/metabolismo , Transducción de Señal , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Hormona Antimülleriana/genética , Axones/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/metabolismo , Células COS , Movimiento Celular , Chlorocebus aethiops , Femenino , Fertilidad , Feto/metabolismo , Heterocigoto , Humanos , Mutación con Pérdida de Función , Hormona Luteinizante/metabolismo , Masculino , Ratones Endogámicos C57BL , Bulbo Olfatorio/metabolismo , Linaje , Receptores de Factores de Crecimiento Transformadores beta/deficiencia , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Adulto Joven
9.
Molecules ; 23(8)2018 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-30103421

RESUMEN

Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1⁻3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1⁻3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Purinas/síntesis química , Purinas/farmacología , Antineoplásicos/química , Neoplasias de la Mama , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Química Sintética , Neoplasias Colorrectales , Femenino , Humanos , Masculino , Microondas , Estructura Molecular , Purinas/química , Relación Estructura-Actividad
10.
Hum Mol Genet ; 27(2): 359-372, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29202173

RESUMEN

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.


Asunto(s)
Receptor DCC/genética , Hipogonadismo/genética , Netrina-1/genética , Adulto , Estudios de Cohortes , Receptor DCC/metabolismo , Femenino , Dominio de Fibronectina del Tipo III , Hormona Liberadora de Gonadotropina/deficiencia , Humanos , Hipogonadismo/metabolismo , Hipogonadismo/patología , Masculino , Mutación , Netrina-1/metabolismo , Neuronas/metabolismo , Neuronas/patología , Linaje , Secuenciación del Exoma
11.
EMBO Mol Med ; 9(10): 1379-1397, 2017 10.
Artículo en Inglés | MEDLINE | ID: mdl-28754744

RESUMEN

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with ß-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.


Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Síndrome de Kallmann/genética , Proteínas de la Membrana/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Animales , Células COS , Caenorhabditis elegans/genética , Chlorocebus aethiops , Estudios de Cohortes , Femenino , Factores de Crecimiento de Fibroblastos/genética , Hormona Liberadora de Gonadotropina/genética , Células HEK293 , Humanos , Hipotálamo/metabolismo , Proteínas Klotho , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Neuronas/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética
12.
Nat Neurosci ; 19(6): 835-44, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27135215

RESUMEN

A sparse population of a few hundred primarily hypothalamic neurons forms the hub of a complex neuroglial network that controls reproduction in mammals by secreting the 'master molecule' gonadotropin-releasing hormone (GnRH). Timely postnatal changes in GnRH expression are essential for puberty and adult fertility. Here we report that a multilayered microRNA-operated switch with built-in feedback governs increased GnRH expression during the infantile-to-juvenile transition and that impairing microRNA synthesis in GnRH neurons leads to hypogonadotropic hypogonadism and infertility in mice. Two essential components of this switch, miR-200 and miR-155, respectively regulate Zeb1, a repressor of Gnrh transcriptional activators and Gnrh itself, and Cebpb, a nitric oxide-mediated repressor of Gnrh that acts both directly and through Zeb1, in GnRH neurons. This alteration in the delicate balance between inductive and repressive signals induces the normal GnRH-fuelled run-up to correct puberty initiation, and interfering with this process disrupts the neuroendocrine control of reproduction.


Asunto(s)
Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , MicroARNs/metabolismo , Reproducción/fisiología , Maduración Sexual/fisiología , Envejecimiento , Animales , Fertilidad/fisiología , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos
13.
Nat Commun ; 7: 10055, 2016 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-26753790

RESUMEN

Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic-pituitary-gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining in vivo and in vitro experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS.


Asunto(s)
Hormona Antimülleriana/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Neuronas/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Receptores de Péptidos/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Animales , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Hormona Folículo Estimulante/metabolismo , Técnicas de Sustitución del Gen , Humanos , Hipotálamo/citología , Inmunohistoquímica , Técnicas In Vitro , Hormona Luteinizante/metabolismo , Ratones , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
14.
Mol Ecol ; 24(5): 1135-49, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25683348

RESUMEN

The microbiome can significantly impact host phenotypes and serve as an additional source of heritable genetic variation. While patterns across eukaryotes are consistent with a role for symbiotic microbes in host macroevolution, few studies have examined symbiont-driven host evolution or the ecological implications of a dynamic microbiome across temporal, spatial or ecological scales. The pea aphid, Acyrthosiphon pisum, and its eight heritable bacterial endosymbionts have served as a model for studies on symbiosis and its potential contributions to host ecology and evolution. But we know little about the natural dynamics or ecological impacts of the heritable microbiome of this cosmopolitan insect pest. Here we report seasonal shifts in the frequencies of heritable defensive bacteria from natural pea aphid populations across two host races and geographic regions. Microbiome dynamics were consistent with symbiont responses to host-level selection and findings from one population suggested symbiont-driven adaptation to seasonally changing parasitoid pressures. Conversely, symbiont levels were negatively correlated with enemy-driven mortality when measured across host races, suggesting important ecological impacts of host race microbiome divergence. Rapid drops in symbiont frequencies following seasonal peaks suggest microbiome instability in several populations, with potentially large costs of 'superinfection' under certain environmental conditions. In summary, the realization of several laboratory-derived, a priori expectations suggests important natural impacts of defensive symbionts in host-enemy eco-evolutionary feedbacks. Yet negative findings and unanticipated correlations suggest complexities within this system may limit or obscure symbiont-driven contemporary evolution, a finding of broad significance given the widespread nature of defensive microbes across plants and animals.


Asunto(s)
Adaptación Biológica/genética , Áfidos/microbiología , Enterobacteriaceae/clasificación , Microbiota , Estaciones del Año , Animales , Enterobacteriaceae/genética , Repeticiones de Microsatélite , Datos de Secuencia Molecular , New England , Análisis de Secuencia de ADN , Simbiosis , Temperatura
15.
Nat Commun ; 6: 6385, 2015 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-25721933

RESUMEN

Reproductive competence in mammals depends on the projection of gonadotropin-releasing hormone (GnRH) neurons to the hypothalamic median eminence (ME) and the timely release of GnRH into the hypothalamic-pituitary-gonadal axis. In adult rodents, GnRH neurons and the specialized glial cells named tanycytes periodically undergo cytoskeletal plasticity. However, the mechanisms that regulate this plasticity are still largely unknown. We demonstrate that Semaphorin7A, expressed by tanycytes, plays a dual role, inducing the retraction of GnRH terminals and promoting their ensheathment by tanycytic end feet via the receptors PlexinC1 and Itgb1, respectively. Moreover, Semaphorin7A expression is regulated during the oestrous cycle by the fluctuating levels of gonadal steroids. Genetic invalidation of Semaphorin7A receptors in mice induces neuronal and glial rearrangements in the ME and abolishes normal oestrous cyclicity and fertility. These results show a role for Semaphorin7A signalling in mediating periodic neuroglial remodelling in the adult ME during the ovarian cycle.


Asunto(s)
Antígenos CD/farmacología , Eminencia Media/fisiología , Neuroglía/metabolismo , Plasticidad Neuronal/fisiología , Semaforinas/farmacología , Análisis de Varianza , Animales , Antígenos CD/administración & dosificación , Western Blotting , Ensayo de Inmunoadsorción Enzimática , Estradiol/análogos & derivados , Femenino , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Ratones , Plasticidad Neuronal/efectos de los fármacos , Ovariectomía , Progesterona , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Semaforinas/administración & dosificación
16.
PLoS Biol ; 12(3): e1001808, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24618750

RESUMEN

Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3aloxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction.


Asunto(s)
Encéfalo/metabolismo , Células Endoteliales/metabolismo , Fertilidad/fisiología , Neuropilina-1/fisiología , Semaforina-3A/metabolismo , Animales , Axones/metabolismo , Axones/ultraestructura , Ciclo Estral/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Hormona Liberadora de Gonadotropina/fisiología , Ligandos , Hormona Luteinizante/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuropilina-1/metabolismo , Ratas , Ratas Sprague-Dawley , Semaforina-3A/genética , Semaforina-3A/fisiología , Transducción de Señal
17.
Front Endocrinol (Lausanne) ; 4: 133, 2013 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-24065959

RESUMEN

The semaphorin proteins are among the best-studied families of guidance cues, contributing to morphogenesis and homeostasis in a wide range of tissue types. The major semaphorin receptors are plexins and neuropilins, however other receptors and co-receptors are capable to mediate signaling by semaphorins. These guidance proteins were originally identified as growth cone "collapsing factors" or as inhibitory signals, crucial for nervous system development. Since those seminal discoveries, the list of functions of semaphorins has rapidly grown. Over the past few years, a growing body of data indicates that semaphorins are involved in the regulation of the immune and vascular systems, in tumor growth/cancer cell metastasis and in neural circuit formation. Recently there has been increasing emphasis on research to determine the potential influence of semaphorins on the development and homeostasis of hormone systems and how circulating reproductive hormones regulate their expression and functions. Here, we focus on the emerging role of semaphorins in the development, differentiation and plasticity of unique neurons that secrete gonadotropin-releasing hormone (GnRH), which are essential for the acquisition and maintenance of reproductive competence in all vertebrates. Genetic evidence is also provided showing that insufficient semaphorin signaling contributes to some forms of reproductive disorders in humans, characterized by the reduction or failure of sexual competence. Finally, we will review some studies with the goal of highlighting how the expression of semaphorins and their receptors might be regulated by gonadal hormones in physiological and pathological conditions.

18.
Cell Metab ; 17(4): 607-17, 2013 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-23562080

RESUMEN

The delivery of blood-borne molecules conveying metabolic information to neural networks that regulate energy homeostasis is restricted by brain barriers. The fenestrated endothelium of median eminence microvessels and tight junctions between tanycytes together compose one of these. Here, we show that the decrease in blood glucose levels during fasting alters the structural organization of this blood-hypothalamus barrier, resulting in the improved access of metabolic substrates to the arcuate nucleus. These changes are mimicked by 2-deoxyglucose-induced glucoprivation and reversed by raising blood glucose levels after fasting. Furthermore, we show that VEGF-A expression in tanycytes modulates these barrier properties. The neutralization of VEGF signaling blocks fasting-induced barrier remodeling and significantly impairs the physiological response to refeeding. These results implicate glucose in the control of blood-hypothalamus exchanges through a VEGF-dependent mechanism and demonstrate a hitherto unappreciated role for tanycytes and the permeable microvessels associated with them in the adaptive metabolic response to fasting.


Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Barrera Hematoencefálica/metabolismo , Epéndimo/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Desoxiglucosa/farmacología , Epéndimo/citología , Ayuno , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal , Uniones Estrechas/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética
19.
Res Vet Sci ; 94(1): 77-83, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22889553

RESUMEN

In this study, the constitutive and inducible expression of the CYP genes (1A1, 1A2, 1B1, 2B22, 3A22, 3A29 and 3A46), related transcriptional factors (AhR, CAR, PXR, and Nrf2) and the antioxidant enzymes SOD, catalase, GSSH-reductase and GSH-peroxidase were investigated in the liver, heart regions and coronary arteries of control pigs and pigs treated with ß-naphthoflavone (ßNF) or with rifampicin (RIF). Real-time PCR experiments and enzymatic or immunoblot assays showed that CYP1A1 was predominantly enhanced by ßNF in a similar manner in all the heart regions, whereas antioxidant enzyme activity was not affected. The rifampicin treatment resulted in an induction of CYP2B22 and CYP3As, at the transcriptional, activity and protein level in liver but not in heart nor in the coronary arteries, despite the expression of CAR and PXR in the cardiac tissues. These results obtained in vivo suggest that pig cardiac tissues may represent a useful model for humans.


Asunto(s)
Hidrocarburo de Aril Hidroxilasas/biosíntesis , Vasos Coronarios/efectos de los fármacos , Citocromo P-450 CYP1A1/biosíntesis , Citocromo P-450 CYP1A2/biosíntesis , Citocromo P-450 CYP3A/biosíntesis , Sistema Enzimático del Citocromo P-450/biosíntesis , Corazón/efectos de los fármacos , Miocardio/metabolismo , Rifampin/farmacología , beta-naftoflavona/farmacología , Animales , Catalasa/biosíntesis , Vasos Coronarios/metabolismo , Citocromo P-450 CYP1B1 , Inducción Enzimática/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa/veterinaria , Superóxido Dismutasa/biosíntesis , Porcinos/metabolismo
20.
Hum Mol Genet ; 20(24): 4759-74, 2011 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-21903667

RESUMEN

Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypogonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual competence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors ß1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeronasal fibers. Disruption of Sema7A function in vitro inhibits ß1-integrin-mediated migration. Analysis of Plexin C1(-/-) mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through ß1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of the GnRH-1 system in mice and as a genetic marker for the elucidation of some forms of GnRH-1 deficiency in humans.


Asunto(s)
Antígenos CD/metabolismo , Movimiento Celular , Fertilidad , Hormona Liberadora de Gonadotropina/metabolismo , Gónadas/embriología , Integrina beta1/metabolismo , Precursores de Proteínas/metabolismo , Semaforinas/metabolismo , Transducción de Señal , Animales , Axones/metabolismo , Encéfalo/embriología , Encéfalo/patología , Recuento de Células , Gónadas/anomalías , Gónadas/metabolismo , Gónadas/patología , Humanos , Masculino , Ratones , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Bulbo Olfatorio/embriología , Bulbo Olfatorio/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/deficiencia , Testículo/embriología , Testículo/metabolismo , Testículo/patología , Órgano Vomeronasal/embriología , Órgano Vomeronasal/metabolismo
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