September 2023
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87 Reads
Yearbook of Paediatric Endocrinology
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September 2023
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87 Reads
Yearbook of Paediatric Endocrinology
September 2023
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85 Reads
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5 Citations
Yearbook of Paediatric Endocrinology
June 2023
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59 Reads
October 2022
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172 Reads
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25 Citations
Science Translational Medicine
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.
September 2022
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73 Reads
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4 Citations
Yearbook of Paediatric Endocrinology
September 2022
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532 Reads
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58 Citations
Science
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.
August 2022
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71 Reads
Free Radical Biology and Medicine
March 2022
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157 Reads
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11 Citations
In adult mammals, neural stem cells are localized in three neurogenic regions, the subventricular zone of the lateral ventricle (SVZ), the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the hypothalamus. In the SVZ and the SGZ, neural stem/progenitor cells (NSPCs) express the glial fibrillary acidic protein (GFAP) and selective depletion of these NSPCs drastically decreases cell proliferation in vitro and in vivo. In the hypothalamus, GFAP is expressed by α-tanycytes, which are specialized radial glia-like cells in the wall of the third ventricle also recognized as NSPCs. To explore the role of these hypothalamic GFAP-positive tanycytes, we used transgenic mice expressing herpes simplex virus thymidine kinase (HSV-Tk) under the control of the mouse Gfap promoter and a 4-week intracerebroventricular infusion of the antiviral agent ganciclovir (GCV) which kills dividing cells expressing Tk. While GCV significantly reduced the number and growth of hypothalamus-derived neurospheres from adult transgenic mice in vitro, it causes hypogonadotropic hypogonadism in vivo. The selective death of dividing tanycytes expressing GFAP indeed results in a marked decrease in testosterone levels and testicular weight, as well as vacuolization of the seminiferous tubules and loss of spermatogenesis. Additionally, GCV-treated GFAP-Tk mice show impaired sexual behavior, but no alteration in food intake or body weight. Our results also show that the selective depletion of GFAP-expressing tanycytes leads to a sharp decrease in the number of gonadotropin-releasing hormone (GnRH)-immunoreactive neurons and a blunted LH secretion. Overall, our data show that GFAP-expressing tanycytes play a central role in the regulation of male reproductive function.
August 2021
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115 Reads
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1 Citation
In adult mammals, neural stem cells emerge in three neurogenic regions, the subventricular zone of the lateral ventricle (SVZ), the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the hypothalamus. In the SVZ and the SGZ, neural stem/progenitor cells (NSPCs) express the glial fibrillary acidic protein (GFAP) and selective ablation of these NSPCs drastically decreases cell proliferation in vitro and in vivo . In the hypothalamus, GFAP is expressed by α-tanycytes, which are specialized radial glia-like cells in the wall of the third ventricle. To explore the role of these hypothalamic GFAP-positive tanycytes, we used transgenic mice expressing herpes simplex virus thymidine kinase (HSV-Tk) under the control of the mouse Gfap promoter and 4-week intracerebroventricular infusion of the antiviral agent ganciclovir (GCV) that kills dividing cells expressing Tk. While GCV drastically reduced the number and growth of hypothalamus-derived neurospheres from adult transgenic mice in vitro , it caused hypogonadism in vivo . The selective death of dividing tanycytes expressing GFAP indeed caused a marked decrease in testosterone levels and testicular weight, as well as vacuolization of the seminiferous tubules and loss of spermatogenesis. In addition, GCV-treated GFAP-Tk mice showed impaired sexual behavior, but no alteration in food intake or body weight. Our results also show that the selective ablation of GFAP-expressing tanycytes leads to a sharp decrease in the number of gonadotropin-releasing hormone (GnRH)-immunoreactive neurons and blunted LH secretion. Altogether, our data show that GFAP-expressing tanycytes play a central role in the regulation of male reproductive function. Main points Killing adult hypothalamic GFAP-expressing cells blunts neurosphere formation in vitro and leads to GnRH deficiency and hypogonadism in vivo . This work pinpoints an unreported role of dividing GFAP-expressing tanycytes in reproductive function.
February 2021
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103 Reads
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12 Citations
Neurobiology of Aging
Premenopausal bilateral ovariectomy is considered to be one of the risk factors of Alzheimer's disease (AD). However, the underlying mechanisms remain unclear. Here, we aimed to investigate long-term neurological consequences of ovariectomy in a rodent AD model, TG2576 (TG), and wild-type mice (WT) that underwent an ovariectomy or sham-operation, using in vivo MRI biomarkers. An increase in osmoregulation and energy metabolism biomarkers in the hypothalamus, a decrease in white matter integrity, and a decrease in the resting-state functional connectivity was observed in ovariectomized TG mice compared to sham-operated TG mice. In addition, we observed an increase in functional connectivity in ovariectomized WT mice compared to sham-operated WT mice. Furthermore, genotype (TG vs WT) effects on imaging markers and GFAP immunoreactivity levels were observed, but there was no effect of interaction (Genotype x Surgery) on amyloid-beta-and GFAP immunoreactivity levels. Taken together, our results indicated that both genotype and ovariectomy alters imaging biomarkers associated with AD.
... [79] Gnrhr expression has been reported in the cerebral cortex and hippocampus of mice and rats, with proposed roles in estrogen synthesis, aromatase regulation, and neuronal plasticity. [80,81] The cerebellum, responsible for voluntary motor control, has been shown to express the GnRH receptor (in mice) ...
September 2023
Yearbook of Paediatric Endocrinology
... [46] These include factors regulating GnRH development, migration, and maturation. The most frequently identified candidates include ANOS1, PROK2/PROKR2, and FGFR1 [47] ; regulators of GnRH neuronal activity (TAC3/TACR3, KISS1/KISS1R, NOS1) [48] ; and genes involved in GnRH downstream function (GNRHR, FSHB, LHB) ( Table 1). Individuals are frequently found to have associated neurodevelopmental conditions, including sensorineural hearing loss, anosmia, synkinesis (mirror movements), or hypoplasia of the corpus callosum. ...
October 2022
Science Translational Medicine
... We have recently shown that ablation of dividing NSCs expressing GFAP induces a decrease in hypothalamic neurogenesis in vitro, alters the integrity of αand β-tanycytes throughout the MBH and causes hypogonadotropic hypogonadism in vivo [33], highlighting the critical role of GFAP-expressing tanycytes in hypothalamic neurogenesis and reproduction [33]. Future investigations are warranted to elucidate the role of the parenchymal GFAP-expressing cells. ...
September 2022
Yearbook of Paediatric Endocrinology
... These data, together with the evidence that Oxt is a master gene regulating thermogenesis, made us hypothesize that the dysfunctional Oxt system could trigger sensory deficits in ASD. A role for hypothalamic hormones in sensorial functions has also been recently seen for gonadotropin-releasing hormone (GnRH) for olfactory function, consistent with our data on Oxt [52,53]. Indeed, the integrity of the Oxt system and the expression of Oxtr is essential to maintain the homeostasis of the body. ...
September 2022
Science
... Higher serum GFAP levels may indicate clinical relapses of TIA (5). This case report will focus on the possibility that TAIassociated neuronal GFAP positivity is a staining artifact rather than a pathological consequence of astrocyte damage after traumatically induced axonal injury (6,7). ...
March 2022
... 17 Neurodegenerative changes due to bilateral ovariectomy have been demonstrated in transgenic animal models of AD using imaging. 29,30 Furthermore, greater estrogen exposure such as premenopausal status, longer reproductive span, higher number of children, and use of hormonal contraceptives and menopausal hormone therapies were associated with larger gray matter volumes in women in midlife, and the findings were independent of the APOE ε4 status. 31 Consistent with these prior studies, we found that the abrupt cessation of ovarian hormones in women who underwent early PBO compared to the referent group was associated with lower temporal lobe cortical thickness at older ages, which was independent of APOE ε4 status. ...
February 2021
Neurobiology of Aging
... Mass spectrometry and quantitative proteomics (using iTRAQ labeling) were performed on dissected cortical kidney tissue samples of control, dehydrated and cyclosporine exposed animals as described previously 62 . Kidney cortical tissue samples were ground completely in a protein extraction buffer (8 M urea, 2 M thiourea, 0.1% SDS in 50 mM triethylammonium bicarbonate solution). ...
October 2018
Neurobiology of Aging