Valerie Leysen’s research while affiliated with University of Lille and other places

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Publications (13)


Figure 1. NOS1 expression in the GnRH neuronal system in humans (a) 9-week old human fetus immunolabeling showing migrating GnRH neurons (green) coexpressing NOS1 protein (red) in the nose (arrows upper panels), but not in the ventral forebrain (vfb; lower panels). (b) NOS1 (green), GnRH (blue) and Kisspeptin (red) triple-immunofluorescence in the infundibulum (Inf) of adult human hypothalami. White arrowheads: contacts between NOS1-immunoreactive processes and GnRH neurons. (c) Kisspeptin fibers (red) innervating (white arrows) NOS1 cells. (d) A subpopulation of the kisspeptin neurons (asterisks) co-expressing NOS1 in the infundibulum. Scale bars: 15 μm.
Figure 2. Identification and characterization of NOS1 mutations in CHH probands (a) Lollipop plot illustrating the distribution of identified mutations in functional domains (blue boxes) of the human NOS1 protein (upper panel) and in highly constrained subregions (LIMBR score < 5%; lower panel in red). (b) Pedigrees of CHH probands harboring NOS1 mutations. Phenotypes are indicated by symbols as shown in the legend (bottom). (c) Representative western blot showing ectopic expression of NOS1 protein (Anti-Myc tag) in HEK293 cells 48h after transfection with WT or mutant NOS1 constructs.
Figure 3. A role for Nos1 in GnRH neuron migration and number (a) Immunolabeling of a mouse embryo on embryonic day (E) 14.5 showing migrating GnRH neurons (green) and Nos1 protein expression (red) in the nose (upper panels) and the ventral forebrain (vfb) (lower panels). (b) Schematic showing in utero injections of L-NAME into the nose of mouse embryos at E12. (c) Immunolabeling of a mouse embryo on E14.5 injected with vehicle (left panels) or L-NAME (right panels) showing migrating GnRH neurons (green) in the nose (upper panels) and the vfb (lower panels). (d) Distribution and (e) total number of GnRH neurons at E14.5 in vehicle (white; n=5)-and L-NAME-treated (red; n=4) embryos in the nose, olfactory bulb (ob) and vfb.
Figure 4. Behavioral tests in Nos1-deficient mice: olfaction, cognition and hearing.
Figure 5. Nos1 activity controls infantile GnRH neuronal function.

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NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice
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September 2023

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87 Reads

Yearbook of Paediatric Endocrinology

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Figure 2: SOX10 protein domains and positions of SOX10 RSVs identified in IHH, WS and gnomAD. Heterozygous loss-of-function alleles are shown in red circles; heterozygous missense alleles are shown in black circles; homozygous missense alleles are shown in green circles. *Only single nucleotide variants associated with WS are shown and SOX10 structural variants are not depicted. DM, Dimerization Domain; HMG, High Mobility Group; Cons, Conserved in SOX-E Family; TA, Transactivation Domain
NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

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.



GnRH replacement rescues cognition in Down syndrome

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.



Selective Depletion of Adult GFAP-Expressing Tanycytes Leads to Hypogonadotropic Hypogonadism in Males

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.


Selective ablation of adult GFAP-expressing tanycytes leads to hypogonadotropic hypogonadism in males

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.


Figure 2. Mean metabolite concentrations (µmol/g) from the hypothalamus, cerebral cortex, and hippocampus of 18-month-old TGOVX (filled bars with red color), TGSHAM (stripped bars with red color), WTSHAM (stripped bar with black color), WTOVX (filled bars with gray color) mice. Two-way ANOVA revealed significant main effects (genotype (horizontal line with red color), surgery (horizontal line with blue color) and interaction (genotype x surgery, horizontal line with green color). For p-values and descriptive statistics (number of animals, mean and standard deviations) see Supplementary Table 1, 2 and 3. Abbreviations: TGOVX, transgenic ovariectomized; TGSHAM, transgenic shamoperated; WTOVX, wild-type ovariectomized; WTSHAM, wildtype sham-operated; Cr, creatine; PCr , phosphocreatine; GABA , γ-aminobutyric acid; Glu, glutamate; Gln, glutamine; GSH, glutathione; Glx, GPC (glycerophosphorylcholine) + PCh (phosphorylcholine); Ins, myoinositol; tNAA, NAA (Nacetylaspartate) + NAAG (Nacetylaspartylglutamate); Error bar indicates standard deviation.
Figure 3. Mean DTI indices of white matter structures (A (sCC), B (FI), C (EC), D (AC)) of sham-operated and OVX WT and TG mice. Significant effects are indicated as (Surgery, S; Genotype, G) and interaction (GxS). Black lines indicate significant results based on post hoc t tests (FDR corrected p values). Abbreviations: AD= axial diffusivity, TG=transgenic, WT=wildtype, OVX=Ovariectomized, SHAM= shamoperated, sCC= Splenium of corpus callosum, FI= Fimbria, AC= Anterior commissure, EC= External capsule; FA, fractional anisotropy is a ratio quantity and has no unit; AxD, Axial diffusivity; RD, radial diffusivity; MD, mean diffusivity; NS, non-significant. Values are mean ± standard deviation.
Fig. 4. (A) Resting-state functional connection (FC) based correlation matrices of 18-month-old ovariectomized (OVX) (Top-right) or sham (Bottom-left) operated TG and WT groups. The colours within of the FC matrices represent z-transformed correlation of the BOLD time series between each pair of region of interests (ROIs). (B) Statistical analyses of FC is shown as a binary matrix, indicating statistically significant effect (after FDR correction) of genotype (green box) (Top-right), surgery (gray box) (Bottom-left) and interaction (blue box) (Top-right) for each ROI-ROI connection. (C) Group averaged statistical FC maps obtained from a seed-based analysis at 18 months with the right anterior cingulate cortex as seed (represented by the blue arrow) are presented for WT and TG. (D) Post-hoc t test were performed based on significant interaction effect (p < 0.05, significant after multiple comparison correction). Black lines indicate significant differences between groups (i.e., TGOVX, TGSHAM, WTOVX, WTSHAM) p value of each significant interaction (Genotype (G) × Surgery (S)) are depicted under each graph (Figure D). Bar graphs indicate the mean values, and the error bars indicates standard error of the mean. Number of animals per group: WTSHAM/OVX: N = 7/8; TGSHAM/OVX: N = 6/7. Abbreviations: Cg_a1, cingulate cortex area 1; Cg_a2, cingulate cortex area 2; CpU, caudate putamen; dHC, dorsal hippocampus; HT, hypothalamus; L, left; MC, motor cortex; PFC, prefrontal cortex; Pta, parietal association area; R, right; RSC, retrosplenial cortex; TH, thalamus; TG, transgenic mice; vHC, ventral hippocampus; WT, wild-type mice; correlations, z-transformed functional connectivity scores.
Figure 5. A representative GFAP and Iba1 merged image showing activated glia cells (see white arrow, green color is for GFAP, red color is for Iba1) in the cortex (A). A representative Nissl staining of brain slides (from the Allen Mouse Brain Atlas) is showing location of regions of interest used for quantitative analysis (B). Quantification of immunofluorescence staining for GFAP in gray matter regions (cingulate, hippocampus, hypothalamus) and white matter regions (corpus callosum and external capsule) in 18-month-old SHAM or OVX treated wild-type (WT) and TG2576 (TG) mice (TGOVX, N=8; TGSHAM, N=5; WTOVX, N=5;WTSHAM, N=6) (A). (C). Two-way ANOVA was performed to investigate the main effects (Genotype (G), Surgery (S)) and interaction (GxT). The FDR adjusted p values are given in boxes on each graph. Abbreviations: GFAP, glial fibrillary acidic protein staining astrocytes; IBA1, allograft inflammatory factor 1 staining microglia; OVX, ovariectomized; SHAM, sham-operated; WT, wildtype mice; TG, TG2576 mice; Cg, cingulate; RSC, retrosplenial cortex; HC, hippocampus; EC, external capsule; HT, hypothalamus; CC, corpus callosum. Bar graphs indicate group mean and error bars indicate standard deviation.
Figure 6. Fluorescence microscopy showing a representative brain section of ovariectomized (TGOVX) and sham-operated (TGSHAM) 18-month-old Tg2576 mice. Aβ aggregates appear light green on the sections (A). Quantification of Aβ aggregates (thioflavin-S fluorescence staining) in the cortex, hippocampus and white matter (corpus callosum and external capsule) (TGOVX, N=6-7; TGSHAM, N=4-6)) (B). Tissue Aβ42 (ELISA) was quantified from the whole brain tissue of 18-month-old SHAM or OVX treated TG mice (p<0.05, two tailed Student's t-test) (TGOVX, N=9; TGSHAM, N=4) (C). Two-way ANOVA indicates a statistically significant (p<0.001) effect of surgery(S) on Luteinizing hormone level (LH) whereby ovariectomized mice had higher level of LH compared to sham-operated mice (Age of mice is between 16-and 18-mont-old, N= 9-11 per group). Bar graphs indicate the mean values and the error bars indicate standard deviation. Abbreviations: GFAP, glial fibrillary acidic protein staining astrocytes; IBA-1, allograft inflammatory factor 1 staining microglia; OVX, ovariectomized; SHAM, sham-operated; CX, cortex; HC, hippocampus. Bar graphs: Mean ± SD.
Long-term ovarian hormone deprivation alters functional connectivity, brain neurochemical profile and white matter integrity in the Tg2576 amyloid mouse model of Alzheimer's disease

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.


Citations (7)


... [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) ...

Reference:

Disorders of puberty and neurodevelopment: A shared etiology?
GnRH replacement rescues cognition in Down syndrome
  • Citing Article
  • 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. ...

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice

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. ...

Selective depletion of adult GFAP-expressing tanycytes leads to hypogonadotropic hypogonadism in males

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. ...

GnRH replacement rescues cognition in Down syndrome
  • Citing Article
  • 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). ...

Selective Depletion of Adult GFAP-Expressing Tanycytes Leads to Hypogonadotropic Hypogonadism in Males

... 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. ...

Long-term ovarian hormone deprivation alters functional connectivity, brain neurochemical profile and white matter integrity in the Tg2576 amyloid mouse model of Alzheimer's disease

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). ...

Image-guided phenotyping of ovariectomized mice: altered functional connectivity, cognition, myelination and dopaminergic functionality
  • Citing Article
  • October 2018

Neurobiology of Aging