28 results on '"Moons, Lieve"'
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2. Additional file 4 of Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons
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Andries, Lien, Kancheva, Daliya, Masin, Luca, Scheyltjens, Isabelle, Van Hove, Hannah, De Vlaminck, Karen, Bergmans, Steven, Claes, Marie, De Groef, Lies, Moons, Lieve, and Movahedi, Kiavash
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Additional file 4. Expression of pro-regenerative genes in cluster MDM7. Gene ontology analysis on the upregulated genes in Mg5 versus Mg2> 20; log2>1) showing the top 20 enriched GO terms for Mg5.
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- 2023
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3. Additional file 5 of Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons
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Andries, Lien, Kancheva, Daliya, Masin, Luca, Scheyltjens, Isabelle, Van Hove, Hannah, De Vlaminck, Karen, Bergmans, Steven, Claes, Marie, De Groef, Lies, Moons, Lieve, and Movahedi, Kiavash
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Additional file 5. Nichenet analysis of MDMs against injured RGCs. A Overview of potential receptors on the retinal ganglion cells of the ligands expressed by the different macrophage clusters. The colourrepresents the regulatory potential of the receptors based on the prior model of ligand-receptor interactions.Receptor expression in the different retinal ganglion cell populations is shown with the colourrepresenting the scaled average expression in the corresponding cluster. B Overview of the predicted target genes in the retinal ganglion cells of the ligands expressed by the different macrophage clusters. The colourrepresents the regulatory potential of the target genes based on the prior model of ligand-target gene interactions. C Circle plot of potential ligand-receptor pairs. It shows the links between predicted ligands from the different monocyte-derived macrophage clusters of the regenerating retinawith their associated receptors found on alpha- and intrinsically photosensitive retinal ganglion cells.
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- 2023
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4. Additional file 1 of Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons
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Andries, Lien, Kancheva, Daliya, Masin, Luca, Scheyltjens, Isabelle, Van Hove, Hannah, De Vlaminck, Karen, Bergmans, Steven, Claes, Marie, De Groef, Lies, Moons, Lieve, and Movahedi, Kiavash
- Abstract
Additional file 1. scRNA-seq of CD45+CD11b+ cells from naïve or ONC retinas. A UMAP showing all CD11b+ cells profiled from the healthy and ONC retinas. BAM, border associated macrophage, cDC: conventional dendritic cell, migDC: migratory dendritic cell, MDM: monocyte-derived macrophage, Mg: microglia, MO, monocyte, N: neutrophils, NK: natural killer cell. B UMAPs showing the expression of the indicated genes. Red line highlights the putative macrophage-neutrophil doublets. C Volcano plot displaying differential expression between Mg3 and Mg1. Genes with adjusted p-value 1 are shown in red. D Volcano plot displaying differential expression between Mg4 and Mg1. Genes with adjusted p-value 1 are shown in red. E Quantification of the density and activityof microglia in retina at different timepoints after ONC corresponding with images shown in figure 1E. Data are shown as mean ± SEM. Repeated measures one-way ANOVA followed by Tukey’s multiple comparisons test, statistical significance between different timepoints is indicated using different letters: conditions that share the same letter are not significantly different, while conditions with different letters are significantly different from each other. n=3-4 mice per condition. F UMAPs showing the expression of the indicated genes, corresponding to the dataset shown in S1A.
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- 2023
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5. Additional file 3 of Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons
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Andries, Lien, Kancheva, Daliya, Masin, Luca, Scheyltjens, Isabelle, Van Hove, Hannah, De Vlaminck, Karen, Bergmans, Steven, Claes, Marie, De Groef, Lies, Moons, Lieve, and Movahedi, Kiavash
- Abstract
Additional file 3. Full scRNA-seq dataset of naïve, ONC and ONC+P3C CD11b+CD45+ cells. A UMAP and cluster annotation showing 22081 cells of both healthy, injuredand regeneratingretinas. BAM, border associated macrophage, cDC: conventional dendritic cell, migDC: migratory dendritic cell, MDM: monocyte-derived macrophage, Mg: microglia, MO, monocyte, N: neutrophils, NK: natural killer cell. B,C UMAP showing 6997 cells of retinas at 4dpi ONC+P3Cand 7956 cells of retinas at 8dpi ONC+P3C. Individual pie charts show the distribution of neutrophils, monocytes or alle immune populations. Numbers in the pie chart are percentages of the cells from the corresponding cluster.
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- 2023
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6. Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer’s disease
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Coninx, Emma, Chew, Yap Ching, Xiaojing, Yang, Wei, Guo, Coolkens, Amelie, Baatout, Sarah, Moons, Lieve, Verslegers, Mieke, and Quintens, Roel
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Cerebral Cortex ,Male ,DNA methylation ,hippocampus ,Alzheimer's disease ,Epigenesis, Genetic ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,cortex ,Alzheimer Disease ,Biological Clocks ,Animals ,Female ,epigenetic clock ,Research Paper - Abstract
Epigenetic clocks are based on age-associated changes in DNA methylation of CpG-sites, which can accurately measure chronological age in different species. Recently, several studies have indicated that the difference between chronological and epigenetic age, defined as the age acceleration, could reflect biological age indicating functional decline and age-associated diseases. In humans, an epigenetic clock associated Alzheimer's disease (AD) pathology with an acceleration of the epigenetic age. In this study, we developed and validated two mouse brain region-specific epigenetic clocks from the C57BL/6J hippocampus and cerebral cortex. Both clocks, which could successfully estimate chronological age, were further validated in a widely used mouse model for AD, the triple transgenic AD (3xTg-AD) mouse. We observed an epigenetic age acceleration indicating an increased biological age for the 3xTg-AD mice compared to non-pathological C57BL/6J mice, which was more pronounced in the cortex as compared to the hippocampus. Genomic region enrichment analysis revealed that age-dependent CpGs were enriched in genes related to developmental, aging-related, neuronal and neurodegenerative functions. Due to the limited access of human brain tissues, these epigenetic clocks specific for mouse cortex and hippocampus might be important in further unravelling the role of epigenetic mechanisms underlying AD pathology or brain aging in general. ispartof: Aging vol:12 issue:20 pages:20817-20834 ispartof: location:United States status: published
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- 2020
7. Additional file 1 of The AppNL-G-F mouse retina is a site for preclinical Alzheimer’s disease diagnosis and research
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Vandenabeele, Marjan, Veys, Lien, Lemmens, Sophie, Hadoux, Xavier, Gelders, Géraldine, Masin, Luca, Lutgarde Serneels, Theunis, Jan, Saito, Takashi, Takaomi C. Saido, Murali Jayapala, Boever, Patrick De, Strooper, Bart De, Stalmans, Ingeborg, Wijngaarden, Peter Van, Moons, Lieve, and Groef, Lies De
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Additional file 1: Supplementary figures
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- 2021
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8. Single-cell transcriptomics analysis of Akimba retina reveals cell type-specific insights into the pathology of diabetic retinopathy
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Van Hove, inge, De Groef, Lies, Boeckx, Bram, Modave, Elodie, Hu, Tjing, Beets, Karen, Etienne, Isabelle, Van Bergen, Tine, Lambrechts, Diether, Moons, Lieve, Feyen, Jean, and Porcu, Michael
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sense organs - Abstract
AIM: Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Despite recent advances, our understanding of its pathophysiology remains incomplete. The aim of this study was to provide deeper insight into the complex network of molecular and cellular changes that underlie diabetic retinopathy by systematically mapping the transcriptional changes that occur in the different cellular compartments of the degenerating diabetic mouse retina. METHODS: Single-cell RNA sequencing was performed on retinal tissue from 12-week-old wild-type and Akimba (Ins2AkitaxVEGF+/-) mice, which are known to replicate features of clinical diabetic retinopathy. This resulted into transcriptome data for 9474 retinal cells, which could be annotated to 8 distinct retinal cell types. Using STRING analysis, we studied differentially expressed gene networks in neuronal, glial and immune cell compartments to create a comprehensive view on the pathological changes that occur in the Akimba retina. Using subclustering analysis, we further characterized macroglial and inflammatory cell subpopulations. Prominent findings were confirmed on protein level using immunohistochemistry, Western blotting and ELISA. RESULTS: At 12 weeks, the Akimba retina was found to display degeneration of rod photoreceptors and presence of inflammatory cells, identified by subclustering analysis as monocyte, macrophage and microglial populations. Analysis of differential expressed genes in the rod, cone, bipolar cell and macroglial compartments indicated changes in cell metabolism and ribosomal gene expression, gliosis, activation of immune system pathways and redox and metal ion dyshomeostasis. Experiments on protein level supported a metabolic shift from glycolysis to oxidative phosphorylation (GAPDH), activation of microglia/macrophages (Isolectin-B4), metal ion and oxidative stress response (metallothionein and heme oxygenase-1) and reactive macroglia (GFAP and S100) in the Akimba retina, as compared to wild-type mice. Our single-cell approach also indicates macroglial subpopulations with distinct fibrotic, inflammatory and gliotic profiles. CONCLUSION: Our study identifies molecular pathways underlying inflammatory, metabolic and oxidative stress-mediated changes in the Akimba mouse model of diabetic retinopathy and distinguishes distinct functional subtypes of inflammatory and macroglial cells. ispartof: Diabetologia vol:63 issue:10 pages:2235-2248 ispartof: location:Germany status: published
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- 2020
9. Additional file 2 of Combination of snapshot hyperspectral retinal imaging and optical coherence tomography to identify Alzheimer’s disease patients
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Lemmens, Sophie, Craenendonck, Toon Van, Eijgen, Jan Van, Groef, Lies De, Bruffaerts, Rose, Jesus, Danilo Andrade De, Charle, Wouter, Murali Jayapala, Sunaric-Mégevand, Gordana, Standaert, Arnout, Theunis, Jan, Keer, Karel Van, Vandenbulcke, Mathieu, Moons, Lieve, Vandenberghe, Rik, Boever, Patrick De, and Stalmans, Ingeborg
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Additional file 2. Details on hyperspectral image analysis.
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- 2020
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10. Additional file 2 of Combination of snapshot hyperspectral retinal imaging and optical coherence tomography to identify Alzheimer’s disease patients
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Lemmens, Sophie, Craenendonck, Toon Van, Eijgen, Jan Van, Groef, Lies De, Bruffaerts, Rose, Jesus, Danilo Andrade De, Charle, Wouter, Murali Jayapala, Sunaric-Mégevand, Gordana, Standaert, Arnout, Theunis, Jan, Keer, Karel Van, Vandenbulcke, Mathieu, Moons, Lieve, Vandenberghe, Rik, Boever, Patrick De, and Stalmans, Ingeborg
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Additional file 2. Details on hyperspectral image analysis.
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- 2020
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11. Neuroinflammation as Fuel for Axonal Regeneration in the Injured Vertebrate Central Nervous System
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Bollaerts, Ilse, Van houcke, Jessie, Andries, Lien, De Groef, Lies, and Moons, Lieve
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Article Subject - Abstract
Damage to the central nervous system (CNS) is one of the leading causes of morbidity and mortality in elderly, as repair after lesions or neurodegenerative disease usually fails because of the limited capacity of CNS regeneration. The causes underlying this limited regenerative potential are multifactorial, but one critical aspect is neuroinflammation. Although classically considered as harmful, it is now becoming increasingly clear that inflammation can also promote regeneration, if the appropriate context is provided. Here, we review the current knowledge on how acute inflammation is intertwined with axonal regeneration, an important component of CNS repair. After optic nerve or spinal cord injury, inflammatory stimulation and/or modification greatly improve the regenerative outcome in rodents. Moreover, the hypothesis of a beneficial role of inflammation is further supported by evidence from adult zebrafish, which possess the remarkable capability to repair CNS lesions and even restore functionality. Lastly, we shed light on the impact of aging processes on the regenerative capacity in the CNS of mammals and zebrafish. As aging not only affects the CNS, but also the immune system, the regeneration potential is expected to further decline in aged individuals, an element that should definitely be considered in the search for novel therapeutic strategies.
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- 2017
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12. Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system
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Lemmens, Kim, Bollaerts, Ilse, Bhumika, Stitipragyan, De Groef, Lies, Van houcke, Jessie, Darras, Veerle, Van Hove, Inge, and Moons, Lieve
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Analysis of Variance ,Nerve Crush ,Neuronal Outgrowth ,matrix metalloproteinases ,axonal regeneration ,Dipeptides ,Matrix Metalloproteinase Inhibitors ,zebrafish ,optic nerve injury ,Gene Expression Regulation, Enzymologic ,Nerve Regeneration ,Disease Models, Animal ,nervous system ,Tubulin ,Optic Nerve Diseases ,Animals ,Visual Pathways ,sense organs - Abstract
Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp-2 and -13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp-2 and -9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp-14 expression decreased during regeneration. Altogether, a phase-dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron-intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472-1493, 2016. © 2015 Wiley Periodicals, Inc. ispartof: Journal of Comparative Neurology vol:524 issue:7 pages:1472-1493 ispartof: location:United States status: published
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- 2016
13. VEGF-D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis
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Koch, Marta, Dettori, Daniela, Van Nuffelen, An, Souffreau, Joris, Marconcini, Lucia, Wallays, Goedele, Moons, Lieve, Bruyère, Françoise, Oliviero, Salvatore, Noel, Agnes, Foidart, Jean-Michel, Carmeliet, Peter, and Dewerchin, Mieke
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- 2009
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14. A proteomic approach to understand MMP?3?driven developmental processes in the postnatal cerebellum: Chaperonin CCT6A and MAP kinase as contributing factors
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Van Hove, Ingrid, Verslegers, Mieke, Hu, Tjing-Tjing, Carden, Martin J., Arckens, Lutgarde, and Moons, Lieve
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RC0321 ,QP506 - Abstract
Matrix metalloproteinase?3 (MMP?3) deficiency in mice was previously reported to result in a transiently retarded granule cell migration at postnatal day 8 (P8) and a sustained disturbed arborization of Purkinje cell dendrites from P8 on, concomitant with a delayed synapse formation between granule cells and Purkinje cells and resulting in mild deficits in motor performance in adult animals. However, the molecular mechanisms by which MMP?3 contributes to proper development of the cerebellar cortex during the first postnatal weeks remains unknown. In this study, we used a functional proteomics approach to investigate alterations in protein expression in postnatal cerebella of wild?type versus MMP?3 deficient mice, and to further elucidate MMP?3?dependent pathways and downstream targets in vivo. At P8, two?dimensional difference gel electrophoresis and mass spectrometry identified 20 unique proteins with a different expression between the two genotypes. Subsequent “Ingenuity Pathway Analysis” and Western blotting indicate that the chaperonin containing T?complex polypeptide 1, subunit 6A and the MAP kinase signaling pathway play a key role in the MMP?3?dependent regulation of neurite outgrowth and neuronal migration in the developing brain.
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- 2015
15. Optogenetic investigation of behavioral responses mediated by the mouse superior colliculus
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Geeraerts Emiel, Dekeyster Eline, Van Den Haute Chris, Mebis Claudia, De Groef Lies, Baekelandt Veerle, and Moons Lieve
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General Neuroscience - Published
- 2015
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16. AMA0428, a novel and potent ROCK inhibitor, as a neuroprotective and regenerative therapy for glaucoma
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Lefevere Evy, Van Hove Inge, De Groef Lies, Sergeys Jurgen, Buyens Tom, Castermans Karolien, Kindt Nele, and Moons Lieve
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General Neuroscience - Published
- 2015
17. Aberrant dendritic patterning in the visual cortex of MMP-3 deficient mice: effects on neurofilament proteins, CRMPs and experience-dependent plasticity
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Aerts Jeroen, Nys Julie, Moons Lieve, Hu Tjing-Tjing, and Arckens Lutgarde
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General Neuroscience - Published
- 2015
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18. The effect of aging on neuroregenerative capacities: insights from the senescent zebrafish retina
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Van Houcke Jessie, Bollaerts Ilse, Beckers An, Lemmens Kim, De Groef Lies, and Moons Lieve
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General Neuroscience - Published
- 2015
19. Assessing the impact of prenatal irradiation in a mouse model: a focus on eye/neural tube development and postnatal viability
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Craenen Kai, Verslegers Mieke, Buset Jasmine, Baatout Sarah, Moons Lieve, and Benotmane Mohammed
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General Neuroscience - Published
- 2015
20. Altered neuronal architecture and plasticity in the visual cortex of MMP-3 deficient mice
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Aerts, Jeroen, Nys, Julie, Smolders, Katrien, Claes, L, Hu, Tjing, Moons, Lieve, and Arckens, Lut
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Male ,Cerebellum ,Histology ,genetic structures ,Biology ,Eye Enucleation ,Neurofilament Proteins ,Apical dendrite ,Cortex (anatomy) ,Neuroplasticity ,medicine ,Animals ,Visual Cortex ,Mice, Knockout ,Neuronal Plasticity ,Neocortex ,Pyramidal Cells ,General Neuroscience ,Long-term potentiation ,Visual cortex ,medicine.anatomical_structure ,Synaptic plasticity ,Matrix Metalloproteinase 3 ,Sensory Deprivation ,Anatomy ,Neuroscience ,Photic Stimulation - Abstract
Matrix metalloproteinases (MMPs) are Zn(2+)-dependent endopeptidases considered to be essential for normal brain development and neuroplasticity by modulating extracellular matrix proteins, receptors, adhesion molecules, growth factors and cytoskeletal proteins. Specifically, MMP-3 has recently been implicated in synaptic plasticity, hippocampus-dependent learning and neuronal development and migration in the cerebellum. However, the function(s) of this enzyme in the neocortex is understudied. Therefore, we explored the phenotypical characteristics of the neuronal architecture and the capacity for experience-dependent cortical plasticity in the visual cortex of adult MMP-3-deficient (MMP-3(-/-)) mice. Golgi-Cox stainings revealed a significant reduction in apical dendritic length and an increased number of apical obliques for layer V pyramidal neurons in the visual cortex of adult MMP-3(-/-) mice compared to wild-type (WT) animals. In addition, a significant upregulation of both phosphorylated and non-phosphorylated neurofilament protein (NF)-high, phosphorylated NF-medium, NF-low and α-internexin was detected in the visual cortex of MMP-3(-/-) mice. To assess the effect of MMP-3 deficiency on cortical plasticity, we monocularly enucleated adult MMP-3(-/-) mice and analyzed the reactivation of the contralateral visual cortex 7 weeks post-enucleation. In contrast to previous results in C57Bl/6J adult mice, activity remained confined to the binocular zone and did not expand into the monocular regions indicative for an aberrant open-eye potentiation. Permanent hypoactivity in the monocular cortex lateral and medial to V1 also indicated a lack of cross-modal plasticity. These observations demonstrate that genetic inactivation of MMP-3 has profound effects on the structural integrity and plasticity response of the visual cortex of adult mice. ispartof: BRAIN STRUCTURE & FUNCTION vol:220 issue:5 pages:2675-2689 ispartof: location:San Diego, CA, USA status: published
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- 2013
21. Receptors for corticotropin-releasing hormone in human pituitary: binding characteristics and autoradiographic localisation to immunocytochemically defined proopiomelanocortin peptides-secreting cells
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Smets, Gerda, Vauquelin, Georges, Moons, Lieve, Smitz, Johan, Kloppel, Gunter, Department of Embryology and Genetics, and Vrije Universiteit Brussel
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- 1991
22. The AppNL-G-F mouse retina is a site for preclinical Alzheimer’s disease diagnosis and research
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Patrick De Boever, Xavier Hadoux, Lieve Moons, Sophie Lemmens, Bart De Strooper, Takaomi C. Saido, Murali Jayapala, Takashi Saito, Lutgarde Serneels, Marjan Vandenabeele, Luca Masin, Lies De Groef, Géraldine Gelders, Lien Veys, Peter van Wijngaarden, Ingeborg Stalmans, Jan Theunis, Vandenabeele, Marjan, Veys, Lien, Lemmens, Sophie, Hadoux, Xavier, Gelders, Geraldine, Masin, Luca, Serneels, Lutgarde, THEUNIS, Jan, Saito, Takashi, Saido, Takaomi C., Jayapala, Murali, DE BOEVER, Patrick, De Strooper, Bart, Stalmans, Ingeborg, van Wijngaarden, Peter, Moons, Lieve, and De Groef, Lies
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medicine.medical_specialty ,Retinal Vein ,Neurology ,Hyperspectral imaging ,lcsh:RC346-429 ,Retina ,Mouse model ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,medicine ,lcsh:Neurology. Diseases of the nervous system ,Microglia ,business.industry ,Neurodegeneration ,Retinal imaging ,Retinal ,Alzheimer's disease ,Electroretinogram ,medicine.disease ,Astrogliosis ,Biomarker (cell) ,medicine.anatomical_structure ,chemistry ,Human medicine ,Neurology (clinical) ,business ,Alzheimer’s disease ,Neuroscience - Abstract
In this study, we report the results of a comprehensive phenotyping of the retina of the App(NL-G-F) mouse. We demonstrate that soluble A beta accumulation is present in the retina of these mice early in life and progresses to A beta plaque formation by midlife. This rising A beta burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings revealed signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the App(NL-G-F) mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal A beta, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the App(NL-G-F) retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD. MV, LV, LuM and LDG are fellows of the Research Foundation Flanders (FWO). This research was supported by the Alzheimer's Research Foundation (SAO-FRA), the European Union Horizon 2020 Research and Innovation Program (2014-2020) (HERALD project, granted by the ATTRAC T consortium). The Centre for Eye Research Australia receives Operational Infrastructure Support from the Victorian Government. XH and PvW acknowledge funding support from the H & L Hecht Trust and the Yulgilbar Alzheimer's Research Program. De Groef, L (corresponding author), Univ Leuven KU Leuven, Dept Biol, Neural Circuit Dev & Regenerat Res Grp, Naamsestr 61,Box 2464, B-3000 Leuven, Belgium. Lies.Degroef@kuleuven.be
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- 2021
23. Combination of snapshot hyperspectral retinal imaging and optical coherence tomography to identify Alzheimer’s disease patients
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Lieve Moons, Karel Van Keer, Jan Theunis, Lies De Groef, Gordana Sunaric-Mégevand, Ingeborg Stalmans, Sophie Lemmens, Wouter Charle, Arnout Standaert, Jan Van Eijgen, Rik Vandenberghe, Mathieu Vandenbulcke, Rose Bruffaerts, Danilo Andrade De Jesus, Toon Van Craenendonck, Murali Jayapala, Patrick De Boever, Theunis, Jan/0000-0002-4191-5667, De Boever, Patrick/0000-0002-5197-8215, Lemmens, Sophie, Van Craenendonck, Toon, Van Eijgen, Jan, De Groef, Lies, BRUFFAERTS, Rose, de Jesus, Danilo Andrade, Charle, Wouter, Jayapala, Murali, Sunaric-Megevand, Gordana, Standaert, Arnout, THEUNIS, Jan, Van Keer, Karel, Vandenbulcke, Mathieu, Moons, Lieve, Vandenberghe, Rik, Stalmans, Ingeborg, and DE BOEVER, Patrick
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Amyloid-beta (Aβ) ,Hyperspectral imaging ,Cognitive Neuroscience ,Nerve fiber layer ,Overfitting ,lcsh:RC346-429 ,Retina ,) ,lcsh:RC321-571 ,s disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Optical coherence tomography ,Alzheimer Disease ,Machine learning ,Medicine ,Humans ,Neurodegeneration ,Alzheimer’ ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,lcsh:Neurology. Diseases of the nervous system ,Receiver operating characteristic ,medicine.diagnostic_test ,business.industry ,Research ,Brain ,Amyloid-beta (Aβ ,Retinal ,Pattern recognition ,Biomarker ,Linear discriminant analysis ,Confidence interval ,medicine.anatomical_structure ,Cognitive impairment ,Neurology ,chemistry ,ROC Curve ,030221 ophthalmology & optometry ,Neurology (clinical) ,Artificial intelligence ,Human medicine ,business ,Alzheimer’s disease ,030217 neurology & neurosurgery ,Biomarkers ,Tomography, Optical Coherence - Abstract
Introduction The eye offers potential for the diagnosis of Alzheimer's disease (AD) with retinal imaging techniques being explored to quantify amyloid accumulation and aspects of neurodegeneration. To assess these changes, this proof-of-concept study combined hyperspectral imaging and optical coherence tomography to build a classification model to differentiate between AD patients and controls. Methods In a memory clinic setting, patients with a diagnosis of clinically probable AD (n = 10) or biomarker-proven AD (n = 7) and controls (n = 22) underwent non-invasive retinal imaging with an easy-to-use hyperspectral snapshot camera that collects information from 16 spectral bands (460-620 nm, 10-nm bandwidth) in one capture. The individuals were also imaged using optical coherence tomography for assessing retinal nerve fiber layer thickness (RNFL). Dedicated image preprocessing analysis was followed by machine learning to discriminate between both groups. Results Hyperspectral data and retinal nerve fiber layer thickness data were used in a linear discriminant classification model to discriminate between AD patients and controls. Nested leave-one-out cross-validation resulted in a fair accuracy, providing an area under the receiver operating characteristic curve of 0.74 (95% confidence interval [0.60-0.89]). Inner loop results showed that the inclusion of the RNFL features resulted in an improvement of the area under the receiver operating characteristic curve: for the most informative region assessed, the average area under the receiver operating characteristic curve was 0.70 (95% confidence interval [0.55, 0.86]) and 0.79 (95% confidence interval [0.65, 0.93]), respectively. The robust statistics used in this study reduces the risk of overfitting and partly compensates for the limited sample size. Conclusions This study in a memory-clinic-based cohort supports the potential of hyperspectral imaging and suggests an added value of combining retinal imaging modalities. Standardization and longitudinal data on fully amyloid-phenotyped cohorts are required to elucidate the relationship between retinal structure and cognitive function and to evaluate the robustness of the classification model. Sophie Lemmens and Jan Van Eijgen are holders of a joint VITO-UZ Leuven PhD grant. Part of this research work has been funded in the context of the VITO-UZ Leuven HERALD project that was granted by the ATTRACT consortium, which received funding from the European Union's Horizon 2020 Research and Innovation Programme (2014-2020). Lies De Groef and Rose Bruffaerts are postdoctoral fellows of the Research Foundation Flanders. Lemmens, S (corresponding author), Univ Hosp UZ Leuven, Dept Ophthalmol, Herestr 49, B-3000 Leuven, Belgium ; Katholieke Univ Leuven, Res Grp Ophthalmol, Biomed Sci Grp, Dept Neurosci, Herestr 49, B-3000 Leuven, Belgium. VITO Flemish Inst Technol Res, Hlth Unit, Boeretang 200, B-2400 Mol, Belgium. sophie.1.lemmens@uzleuven.be
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- 2020
24. Loss of the Cholesterol-Binding Protein Prominin-1/CD133 Causes Disk Dysmorphogenesis and Photoreceptor Degeneration
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Stefan Vinckier, Hideyasu Oh, Naoyuki Tanimoto, Lieve Moons, Michaela Wilsch-Bräuninger, Serena Zacchigna, Mathias W. Seeliger, Ewa Missol-Kolka, Felix Tonagel, Peter Carmeliet, Wieland B. Huttner, Sandra Jansen, József Jászai, Denis Corbeil, Mieke Dewerchin, Zacchigna, Serena, Oh, Hideyasu, Wilsch Bräuninger, Michaela, Missol Kolka, Ewa, Jászai, József, Jansen, Sandra, Tanimoto, Naoyuki, Tonagel, Felix, Seeliger, Mathia, Huttner, Wieland B., Corbeil, Deni, Dewerchin, Mieke, Vinckier, Stefan, Moons, Lieve, and Carmeliet, Peter
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Retinal degeneration ,genetic structures ,Vision ,Apoptosis ,Degeneration (medical) ,Blindness ,Inbred C57BL ,Eye ,Stem cell marker ,Mice ,chemistry.chemical_compound ,AC133 Antigen ,Mice, Knockout ,Genetics ,Endothelial Cell ,Stem Cells ,General Neuroscience ,Retinal Degeneration ,Articles ,female genital diseases and pregnancy complications ,CD ,Cell biology ,Blindne ,Cholesterol ,medicine.anatomical_structure ,Peptide ,Stem cell ,Retinal Pigments ,Degeneration ,Knockout ,Retina ,Animals ,Antigens, CD ,Down-Regulation ,Endothelial Cells ,Genetic Predisposition to Disease ,Glycoproteins ,Mice, Inbred C57BL ,Nerve Degeneration ,Peptides ,Photoreceptor Cells, Vertebrate ,Retinal Artery ,Vision, Ocular ,Neuroscience (all) ,Visual phototransduction ,Biology ,Stem Cell ,Ocular ,Prominin-1 ,medicine ,Photoreceptor Cells ,Antigens ,Retinal Pigment ,Vertebrate ,Animal ,Apoptosi ,Retinal ,medicine.disease ,chemistry ,Glycoprotein - Abstract
Prominin-1/CD133 (Prom-1) is a commonly used marker of neuronal, vascular, hematopoietic and other stem cells, yet little is known about its biological role and importancein vivo. Here, we show that loss of Prom-1 results in progressive degeneration of mature photoreceptors with complete loss of vision. Despite the expression of Prom-1 on endothelial progenitors, photoreceptor degeneration was not attributable to retinal vessel defects, but caused by intrinsic photoreceptor defects in disk formation, outer segment morphogenesis, and associated with visual pigment sorting and phototransduction abnormalities. These findings shed novel insight on how Prom-1 regulates neural retinal development and phototransduction in vertebrates.
- Published
- 2009
25. Glaucoma and the brain: a novel approach towards retinal ganglion cell protection : Glaucoom en de hersenen: een nieuwe benadering ter bescherming van de retinale ganglioncellen
- Author
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Dekeyster, Eline, Arckens, Lut, and Moons, Lieve
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genetic structures ,sense organs ,Glaucoma, Mouse models, Retina, Superior colliculus, Visual cortex, BDNF, Neuroprotection, Viral vector technology, Optogenetics ,eye diseases - Abstract
Summary PhD thesis Eline Dekeyster Glaucoma refers to a group of optic neuropathies, all characterized by progressive degeneration of retinal ganglion cells (RGCs) - the cells that send visual information from the eye to the brain - resulting in a gradual loss of vision. Ocular hypertension (OHT) is considered one of the major risk factors for development and progression of glaucoma, and thus lowering eye pressure through topical application of hypotensive eye drops or surgery, is the cornerstone of glaucoma therapy today. Unfortunately, a number of patients do not benefit from such treatments, and although it generally slows down disease progression, controlling eye pressure does not really halt RGC degeneration. This stresses the need for development of new therapies aimed at long‑term retinal neuroprotection and preservation of vision. Within this context, this PhD project intends to contribute to the knowledge on the pathological mechanisms underlying glaucomatous RGC death and to highlight possible novel strategies towards RGC protection. The first part of this thesis was dedicated to the optimization and characterization of two mouse models of glaucoma: the OHT model and the normotensive optic nerve crush (ONC) model, each focusing on different aspects of the disease. Next, a closer look was taken at the link between glaucoma and the brain. Although long considered purely an eye disease, glaucoma is increasingly becoming recognized as a disease of the entire visual system. Using the OHT model, the effect of elevated eye pressure on the central visual brain areas was evaluated. Reduced RGC synapse density, retinotopically correlated to degeneration of RGC soma, and intensive but transient astroglial reactivity were observed in the main subcortical RGC projection area, which for mice is the superior colliculus (SC). Furthermore, diminished neuronal activity in the primary visual cortex extending to specific extrastriate areas was seen early after OHT induction. Complete recovery of cortical activity over time demonstrated the capacity of the adult visual cortex to functionally reorganize in an attempt to adapt to glaucomatous RGC degeneration. Our results uncovered for the first time effects on visual cortex activity patterns in a murine OHT model and, yet again, highlight the importance of including the brain in glaucoma research. For their survival, RGCs depend on neurotrophic factors, e.g. neurotrophins, produced locally in the eye as well as in the projection areas in the brain, from where they are retrogradely transported along the RGC axons towards the cell bodies in the retina. According to the neurotrophin deprivation hypothesis, diminished retrograde delivery of neurotrophic support during an early stage of glaucoma pathogenesis is one of the main triggers that induce apoptotic signaling in RGCs. Therefore, interfering with neurotrophic signaling seems an attractive tool to achieve neuroprotection. In this PhD project, the well-known neurotrophin brain-derived neurotrophic factor (BDNF) was chosen as the lead molecule to study the role of neurotrophic factors in glaucoma. The levels of BDNF and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), were examined in the retina and SC of mice subjected to OHT or ONC. Both models differentially influenced BDNF and TrkB levels. Defining a specific role for BDNF signaling within glaucoma pathology remains difficult as various studies using a variety of animal models of glaucoma have yielded unique results, including those presented within this manuscript. In line with the hypothesis of deprived neurotrophic support being an important contributor to glaucomatous RGC death, exogenous neurotrophin administration to the eye has been shown to reduce loss of RGCs; however, the neuroprotective effect was mostly transient and insufficient for sustained RGC survival. Therefore, we hypothesized that treatment at the level of extraretinal neurotrophin sources in the brain might be beneficial, as target-derived neurotrophins are likely to induce signaling pathways that diverge from local neurotrophin signaling. Brain-directed treatment was approached in two ways: 1) viral vector-mediated upregulation of BDNF in the SC was used to boost retrograde delivery of BDNF to the retina; 2) a more broad strategy to optogenetically increase neuronal activity in the SC was implemented to enhance production of a whole spectrum of endogenous neurotrophic factors. In light of these hypotheses, viral vector technology was optimized for use in the mouse SC. Although the previously reported temporary neuroprotective effect of intravitreally-delivered recombinant BDNF was confirmed, viral vector-induced overexpression of BDNF in the SC did not lead to protection of the RGCs in our glaucoma models. This unfortunate result most likely resulted from decreased neurotrophin responsiveness upon vector mediated BDNF overexpression. Regarding the second strategy employing SC manipulation to aim for RGC protection, optogenetic methods were introduced and validated. The basic principle underlying optogenetics is the introduction of genes, e.g. through viral vector technology, encoding light-sensitive ion channels or opsins into cells, rendering them responsive to light of a specific wavelength. For the first time, the application of an opsin with specifically slow kinetic properties, the stabilized step-function opsin (SSFO), was validated for use in the mouse SC. A setup for chronic optogenetic stimulation in awake, freely moving animals, was developed, and shown to effectively stimulate collicular activity. Two consecutive behavioral responses were observed upon unilateral SC stimulation, a short escape response, followed by prolonged pursuit-like behavior. In conclusion, a large component of this thesis was dedicated to method optimization, such as the two mouse models of glaucoma, viral vector technology, and a setup for in vivo optogenetic stimulation. These methods will importantly contribute to future research within the research group. Furthermore, new findings on the role of higher order visual brain centers in glaucoma pathogenesis were discovered. Although we were not able to deliver a proof-of-concept for the neurotrophin deprivation hypothesis, important insights concerning the complexity of neurotrophic factor treatments were highlighted. 1 General introduction; 2 Mouse models for glaucoma research; 3 Effects of ocular hypertension on the superior colliculus and visual cortex of mice; 4 Characterization of viral vectors for transgene expression in the mouse superior colliculus; 5 A role for brain-derived neurotrophic factor in glaucoma; 6 Optogenetic stimulation in the mouse superior colliculus; 7 General conclusions and future perspectives nrpages: 217 status: published
- Published
- 2015
26. Matrix metalloproteinase-3: a prerequisite for structural and functional plasticity in the visual cortex of the mouse : Matrix metalloproteinase-3: een voorwaarde voor structurele en functionele plasticiteit in de visuele cortex van de muis
- Author
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Aerts, Jeroen, Moons, Lieve, and Arckens, Lut
- Abstract
The brain is able to change its functional and anatomical organization in responseto environmental changes and this ability is termed neuroplasticity. The visualcortex, the area in the brain that receives visual input, is undoubtedly one of thebest and most studied areas of the brain for understanding cortical plasticity anddevelopment. However, the molecular mechanisms governing cortical plasticityare still elusive. Matrix metalloproteinases (MMPs) are Zn2+-dependentendopeptidases considered to be essential for normal brain development andneuroplasticity by modulating extracellular matrix proteins, receptors, adhesionmolecules, growth factors and cytoskeletal proteins. Specifically, MMP-3 hasrecently been implicated in synaptic plasticity, hippocampus-dependent learningand neuronal development and migration in the cerebellum. However, thefunction of this enzyme in the neocortex is understudied. Therefore, weexplored the phenotypical characteristics of the neuronal architecture andthe capacity for experience-dependent cortical plasticity in the visual cortexof adult MMP-3-deficient (MMP-3-/-) mice. Golgi Cox stainings revealed asignificant reduction in apical dendritic length, spine length and an increasednumber of apical obliques for layer V pyramidal neurons in the visual cortex ofadult MMP-3-/- mice compared to wildtype (WT) animals. To assess the effectof MMP-3 deficiency on cortical plasticity, we monocularly enucleated (ME)adult MMP-3-/- mice and analyzed the reactivation of the contralateral visualcortex seven weeks post-ME. In contrast to previous results in C57Bl/6J adultmice, activity remained confined to the binocular zone and did not expandinto the monocular regions indicative for an aberrant open-eye potentiation.Permanent hypoactivity in the monocular cortex lateral and medial to V1 also indicated a lack of cross-modal plasticity. These observations demonstratethat genetic inactivation of MMP-3 has profound effects on the structuralintegrity and plasticity response of the visual cortex of adult mice. To furtherassess the molecular changes governing the MMP-3-/- cortical phenotype, weperformed Western analysis on different neurofilament protein (NF) subunitsand collapsin response mediator proteins (CRMP). The former are markers fora healthy cytoskeleton and determine the shape and architecture of neuronswhereas CRMPs are mainly involved in regulating neurite outgrowth throughmicrotubule polymerization. A significant upregulation of both phosphorylatedand non-phosphorylated NF-high, phosphorylated NF-medium, NF-low andalfa-internexin was detected in the visual cortex of MMP-3-/- mice comparedwith WT. These results suggest that an altered stoichiometry of NF subunits isrelated to the truncated neuronal architecture observed in MMP-3-/- mice. Inaddition, the expression level of CRMP-5 was significantly elevated in MMP-3-/-samples whereas the levels of CRMP-1, -2, -3 and -4 did not differ compared withWT mice. Recent literature indicates that overexpression of CRMP-5 negativelyregulates dendritic outgrowth by reducing the number of mitochondria throughincreased autophagy and mitophagy. Therefore, we assesed the expression levelof a marker for autophagy, the microtubule-associated protein 1 light chain 3(LC3-II) and found a significant increase in MMP-3-/- samples. The expressionlevels of mitochondrial fusion protein mitofusin-2 (Mfn-2) and dynamin-relatedprotein 1 (Drp1), a mitochondrial fission protein, did not differ, indicating thatthe mitochondrial fusion and fission balance is not altered in the visual cortexof MMP-3-/- mice. Taken together, an altered NF composition, overexpressionof CRMP-5 and a possible upregulation of autophagy underlie the structuralphenotype in the visual cortex of MMP-3-/- mice. To assess the acute role of MMPs in ME-induced visual cortex plasticitywe performed Western analysis for MMP-3 to reveal fluctuations in MMP-3expression level associated with post-ME survival time in P45 and P120 mice.This approach revealed significant differences in proMMP-3 expression especiallyin P45 mice both in the medial monocular and binocular zone whereas in P120mice, enucleation did not induce large effects on proMMP-3 expression. Thissuggests that MMP-3 is potentially necessary to inhibit cross-modal plasticity as normally seen in P45 mice. However, no active form of MMP-3 was visibleusing Western analysis and therefore we tried to optimize a fluorescent activityassay to study MMP-3 proteolysis in visual cortex samples. However, whenperforming this assay on samples of MMP-3-/- mice, a fluorescent signal in thesame range as P45 and P120 ME C57Bl/6J samples was measured, rendering thistechnique unreliable. To extend the analysis of ME-induced cortical plasticityto other MMPs, we focused on the gelatinases (MMP-2 and MMP-9) becausetheir function in synaptic plasticity is well established. Using a combination ofWestern analysis and gelatin zymography we revealed no significant differences inMMP-2 expression in all conditions studied, suggesting that this enzyme does notplay a major role in ME-induced open-eye potentiation or cross-modal plasticity.No suitable antibodies for MMP-9 were available and gelatin zymography didnot reveal detectable levels of MMP-9 proteolytic activity, possibly due tosample preparation issues. To conclude, further research is needed to evaluatethe activity of different MMPs in the mouse visual cortex and this will providea basis for future experiments for pharmacological intervention to establish acausal relationship between MMP function and ME-induced cortical plasticity. nrpages: 186 status: published
- Published
- 2014
27. Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1
- Author
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Mireille Mutin, Ulf Eriksson, Karlien Hermans, Alain Chédotal, Marie-Françoise Belin, Ellen Knevels, Peter Carmeliet, Carmen Ruiz de Almodovar, Claire Meissirel, Stefan Vinckier, Rudi D'Hooge, Naura Chounlamountri, Stijn Stroobants, Jody J. Haigh, Koen Poesen, Nicole Thomasset, Katie Van Geyte, Cathy Coulon, Paul Van Hecke, Bernard Gallez, Bénédicte F. Jordan, Paul A. Salin, Serena Zacchigna, Erik Storkebaum, Tom Dresselaers, Julian Aragones, Joke Dhondt, Julie Renaud, Jérôme Honnorat, Ilse Geudens, David Gall, Serge N. Schiffmann, Lieve Moons, Karel Dassonville, Diether Lambrechts, UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - (SLuc) Service de médecine nucléaire, Institut National de la Santé et de la Recherche Médicale (INSERM), KUL, De Almodovar, Carmen Ruiz, Coulon, Cathy, Salin, Paul Antoine, Knevels, Ellen, Chounlamountri, Naura, Poesen, Koen, Hermans, Karlien, Lambrechts, Diether, Van Geyte, Katie, Dhondt, Joke, Dresselaers, Tom, Renaud, Julie, Aragones, Julian, Zacchigna, Serena, Geudens, Ilse, Gall, David, Stroobants, Stijn, Mutin, Mireille, Dassonville, Karel, Storkebaum, Erik, Jordan, Bénédicte F., Eriksson, Ulf, Moons, Lieve, D'Hooge, Rudi, Haigh, Jody J., Belin, Marie Françoise, Schiffmann, Serge, Van Hecke, Paul, Gallez, Bernard, Vinckier, Stefan, Chédotal, Alain, Honnorat, Jérôme, Thomasset, Nicole, Carmeliet, Peter, and Meissirel, Claire
- Subjects
Neurons - cytology, physiology ,Vascular Endothelial Growth Factor A ,Cerebellum ,Angiogenesis ,[SDV]Life Sciences [q-bio] ,Apoptosis ,Matrix (biology) ,Cerebellum - cytology, physiology ,Transgenic ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,HEK293 Cell ,Cell Movement ,Protein Isoforms ,Vascular Endothelial Growth Factor A - genetics, metabolism ,Apoptosis - physiology ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,Neurons ,0303 health sciences ,Microscopy ,Cultured ,Microscopy, Confocal ,Blotting ,Reverse Transcriptase Polymerase Chain Reaction ,General Neuroscience ,Articles ,Sciences bio-médicales et agricoles ,Growth Cone ,Immunohistochemistry ,Vascular Endothelial Growth Factor Receptor-2 - genetics, metabolism ,Cell biology ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Confocal ,Western ,Human ,Cells ,Protein Isoforms - metabolism ,Blotting, Western ,Growth Cones ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Biology ,03 medical and health sciences ,In vivo ,medicine ,Animals ,Humans ,HEK293 Cells ,Vascular Endothelial Growth Factor Receptor-2 ,Neuroscience (all) ,030304 developmental biology ,Animal ,Growth Cones - metabolism ,Apoptosi ,Protein Isoform ,Neuron ,Granule cell ,Molecular biology ,In vitro ,chemistry ,Vascular Endothelial Growth Factor Receptor-2 -- genetics ,Cell Movement - physiology ,metabolism ,030217 neurology & neurosurgery ,Ex vivo - Abstract
Vascular endothelial growth factor (VEGF) regulates angiogenesis, but also has important, yet poorly characterized roles in neuronal wiring. Using several genetic and in vitro approaches, we discovered a novel role for VEGF in the control of cerebellar granule cell (GC) migration from the external granule cell layer (EGL) toward the Purkinje cell layer (PCL). GCs express the VEGF receptor Flk1, and are chemoattracted by VEGF, whose levels are higher in the PCL than EGL. Lowering VEGF levels in mice in vivo or ectopic VEGF expression in the EGL ex vivo perturbs GC migration. Using GC-specific Flk1 knock-out mice, we provide for the first time in vivo evidence for a direct chemoattractive effect of VEGF on neurons via Flk1 signaling. Finally, using knock-in mice expressing single VEGF isoforms, we show that pericellular deposition of matrix-bound VEGF isoforms around PC dendrites is necessary for proper GC migration in vivo. These findings identify a previously unknown role for VEGF in neuronal migration., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2010
28. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
- Author
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Robert Silasi-Mansat, Pieter Van Noten, Christopher W. Pugh, Florea Lupu, Peter Carmeliet, Julián Aragonés, Peter J. Ratcliffe, Hélène Lemieux, Diether Lambrechts, Tom Dresselaers, A. Grosfeld, Patrick H. Maxwell, Nam Ho Jeoung, Martin Schneider, Lieve Moons, Robert A. Harris, Francis Sluse, Sarah K. Harten, Peter Fraisl, Bernard Gallez, Katie Van Geyte, Phil Salmon, Johan Buyse, Rachel Navet, Massimiliano Mazzone, Paul Van Hecke, Katrien De Bock, Luc Mortelmans, Myriam Baes, Bénédicte F. Jordan, Peter Hespel, Thierry VandenDriessche, Bhathiya Wijeyekoon, Christophe Deroose, Frans Schuit, Mieke Dewerchin, Frans Gorus, Carsten Willam, Marc Tjwa, Peggy Lafuste, Erich Gnaiger, Serena Zacchigna, Paul P. Van Veldhoven, Tammie Bishop, Ruud Dirkx, Johan Nuyts, Antonio Diez-Juan, Aragonés, Julián, Schneider, Martin, Van Geyte, Katie, Fraisl, Peter, Dresselaers, Tom, Mazzone, Massimiliano, Dirkx, Ruud, Zacchigna, Serena, Lemieux, Hélène, Jeoung, Nam Ho, Lambrechts, Diether, Bishop, Tammie, Lafuste, Peggy, Diez Juan, Antonio, Harten, Sarah K., Van Noten, Pieter, De Bock, Katrien, Willam, Carsten, Tjwa, Marc, Grosfeld, Alexandra, Navet, Rachel, Moons, Lieve, Vandendriessche, Thierry, Deroose, Christophe, Wijeyekoon, Bhathiya, Nuyts, Johan, Jordan, Benedicte, Silasi Mansat, Robert, Lupu, Florea, Dewerchin, Mieke, Pugh, Chri, Salmon, Phil, Mortelmans, Luc, Gallez, Bernard, Gorus, Fran, Buyse, Johan, Sluse, Franci, Harris, Robert A., Gnaiger, Erich, Hespel, Peter, Van Hecke, Paul, Schuit, Fran, Van Veldhoven, Paul, Ratcliffe, Peter, Baes, Myriam, Maxwell, Patrick, Carmeliet, Peter, and The Center for Transgene Technology and Gene Therapy, Katholieke Universiteit (K.U.) Leuven, Leuven, B-3000, Belgium
- Subjects
Genetics (clinical) ,Genetics ,Mitochondrion ,medicine.disease_cause ,Mice ,0302 clinical medicine ,Glutamates ,Models ,Carbon Radioisotopes ,Hypoxia ,Tomography ,ComputingMilieux_MISCELLANEOUS ,0303 health sciences ,Carbon Isotopes ,Homozygote ,Skeletal ,Immunohistochemistry ,Mitochondria ,X-Ray Computed ,medicine.anatomical_structure ,Embryo ,030220 oncology & carcinogenesis ,Muscle ,Procollagen-proline dioxygenase ,medicine.symptom ,Oxidation-Reduction ,medicine.medical_specialty ,Nuclear Magnetic Resonance ,Ischemia ,Procollagen-Proline Dioxygenase ,Oxidative phosphorylation ,Carbohydrate metabolism ,Biology ,Models, Biological ,03 medical and health sciences ,Oxygen Consumption ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,Nuclear Magnetic Resonance, Biomolecular ,030304 developmental biology ,Mammalian ,Skeletal muscle ,Hypoxia (medical) ,Carbon Dioxide ,Fibroblasts ,Embryo, Mammalian ,medicine.disease ,Biological ,Energy Metabolism ,Glucose ,Tomography, X-Ray Computed ,Basal Metabolism ,Endocrinology ,Oxidative stress ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Biomolecular - Abstract
HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Pparalpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress. ispartof: Nature Genetics vol:40 issue:2 pages:170-180 ispartof: location:United States status: published
- Published
- 2008
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