The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Ilias Kazanis - One of the best experts on this subject based on the ideXlab platform.
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Subependymal Zone-Derived Oligodendroblasts Respond to Focal Demyelination but Fail to Generate Myelin in Young and Aged Mice
Stem cell reports, 2017Co-Authors: Ilias Kazanis, Kimberley A. Evans, Evangelia Andreopoulou, Christina Dimitriou, Christos Koutsakis, Ragnhildur Thóra Káradóttir, Robin J.m. FranklinAbstract:Two populations of oligodendrogenic progenitors co-exist within the corpus callosum (CC) of the adult mouse. Local, parenchymal oligodendrocyte progenitor cells (pOPCs) and progenitors generated in the Subependymal Zone (SEZ) cytogenic niche. pOPCs are committed perinatally and retain their numbers through self-renewing divisions, while SEZ-derived cells are relatively "young," being constantly born from neural stem cells. We compared the behavior of these populations, labeling SEZ-derived cells using hGFAP:CreErt2 mice, within the homeostatic and regenerating CC of the young-adult and aging brain. We found that SEZ-derived oligodendroglial progenitors have limited self-renewing potential and are therefore not bona fide OPCs but rather "oligodendroblasts" more similar to the neuroblasts of the neurogenic output of the SEZ. In the aged CC their mitotic activity is much reduced, although they still act as a "fast-response element" to focal demyelination. In contrast to pOPCs, they fail to generate mature myelinating oligodendrocytes at all ages studied.
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The late response of rat Subependymal Zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche
Experimental neurology, 2013Co-Authors: Ilias Kazanis, Robin J.m. Franklin, Natalia Gorenkova, Jing-wei Zhao, Michel Modo, Charles Ffrench-constantAbstract:Ischaemia leads to increased proliferation of progenitors in the Subependymal Zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1 h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5 weeks and 1 year after the insult. Neural stem cells (NSCs) responded differently from their downstream progenitors to MCAO, with NSCs being activated only transiently whilst progenitors remain activated even at 1 year post-injury. Importantly, mitotic activation was observed only in the affected areas of the niche and specifically in the dorsal half of the SEZ. Analysis of the topography of mitoses, in relation to the anatomy of the lesion and to the position of ependymal cells and blood vessels, suggested an interplay between lesion-derived recruiting signals and the local signals that normally control proliferation in the chronic post-ischaemic phase.
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The number of stem cells in the Subependymal Zone of the adult rodent brain is correlated with the number of ependymal cells and not with the volume of the niche.
Stem cells and development, 2011Co-Authors: Ilias Kazanis, Charles Ffrench-constantAbstract:The mammalian Subependymal Zone (SEZ; often called subventricular) situated at the lateral walls of the lateral ventricles of the brain contains a pool of relatively quiescent adult neural stem cells whose neurogenic activity persists throughout life. These stem cells are positioned in close proximity both to the ependymal cells that provide the cerebrospinal fluid interface and to the blood vessel endothelial cells, but the relative contribution of these 2 cell types to stem cell regulation remains undetermined. Here, we address this question by analyzing a naturally occurring example of volumetric scaling of the SEZ in a comparison of the mouse SEZ with the larger rat SEZ. Our analysis reveals that the number of stem cells in the SEZ niche is correlated with the number of ependymal cells rather than with the volume, thereby indicating the importance of ependymal-derived factors in the formation and function of the SEZ. The elucidation of the factors generated by ependymal cells that regulate stem cell n...
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quiescence and activation of stem and precursor cell populations in the Subependymal Zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals
The Journal of Neuroscience, 2010Co-Authors: Ilias Kazanis, Justin D Lathia, Tegy J Vadakkan, Eric Raborn, Ruiqian Wan, Mohamed R Mughal, Mark D Eckley, Takako Sasaki, Bruce L Patton, Mark P MattsonAbstract:The Subependymal Zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior. We show that NSCs and precursors proceed through mitosis in the same domains within the SEZ of adult male mice—albeit with NSCs nearer ependymal cells—and that distance from the ventricle is a stronger limiting factor for neurogenic activity than distance from blood vessels. Furthermore, we show that NSCs and precursors are embedded in a laminin-rich extracellular matrix, to which they can both contribute. Importantly, they express differential levels of extracellular matrix receptors, with NSCs expressing low levels of α6β1 integrin, syndecan-1, and lutheran, and in vivo blocking of β1 integrin selectively induced the proliferation and ectopic migration of precursors. Finally, when NSCs are activated to reconstitute the niche after depletion of precursors, expression of laminin receptors is upregulated. These results indicate that the distinct behavior of adult NSCs and precursors is not necessarily regulated via exposure to differential extracellular signals, but rather via intrinsic regulation of their interaction with their microenvironment.
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the Subependymal Zone neurogenic niche a beating heart in the centre of the brain how plastic is adult neurogenesis opportunities for therapy and questions to be addressed
Brain, 2009Co-Authors: Ilias KazanisAbstract:The mammalian brain is a remarkably complex organ comprising millions of neurons, glia and various other cell types. Its impressive cytoarchitecture led to the long standing belief that it is a structurally static organ and thus very sensitive to injury. However, an area of striking structural flexibility has been recently described at the centre of the brain. It is the Subependymal Zone of the lateral wall of the lateral ventricles. The Subependymal Zone—like a beating heart—continuously sends new cells to different areas of the brain: neurons to the olfactory bulbs and glial cells to the cortex and the corpus callosum. Interestingly, the generation and flow of cells changes in response to signals from anatomically remote areas of the brain or even from the external environment of the organism, therefore indicating that Subependymal neurogenesis—as a system—is integrated in the overall homeostatic function of the brain. In this review, it will be attempted to describe the fundamental structural and functional characteristics of the Subependymal neurogenic niche and to summarize the available evidence regarding its plasticity. Special focus is given on issues such as whether adult neural stem cells are activated after neurodegeneration, whether defects in neurogenesis contribute to neuropathological conditions and whether monitoring changes in neurogenic activity can have a diagnostic value.
Cs Weickert - One of the best experts on this subject based on the ideXlab platform.
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Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder.
Schizophrenia bulletin, 2020Co-Authors: Christin Weissleder, Guy Barry, Maree J. Webster, Cs WeickertAbstract:The generation of inhibitory interneurons from neural stem cells in the Subependymal Zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the Subependymal Zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.
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O11.5. INCREASED INFLAMMATION AND MACROPHAGE INFILTRATION IS ASSOCIATED WITH ALTERED Subependymal Zone NEUROGENESIS IN SCHIZOPHRENIA BUT NOT BIPOLAR DISORDER
Schizophrenia Bulletin, 2020Co-Authors: Hayley North, Christin Weissleder, Guy Barry, Maree J. Webster, Mainá Bitar, Janice M. Fullerton, Rachel Sager, Cs WeickertAbstract:Abstract Background Inflammation is implicated in the pathogenesis of schizophrenia and bipolar disorder. Inflammation regulates neurogenesis, and markers for stem cells and neuronal progenitors are reduced in schizophrenia and bipolar disorder in the Subependymal Zone (SEZ) – the brain’s largest region of neurogenesis. This research aimed to discover core differences in gene expression and cellular composition in the SEZ in psychiatric disorders that may contribute to dysregulated neurogenesis. Methods We performed total RNA sequencing in the SEZ of 20 post-mortem schizophrenia and 21 control brains. Quantitative PCR (qPCR) and immunohistochemistry were performed in 32 schizophrenia and 32 control overlapping cases and 29 bipolar disorder cases. Immunohistochemistry was used for quantification and localisation of CD163+ macrophages. Cluster-analysis of IL6, IL6R, IL1R1 and SERPINA3 expression defined low and high inflammation subgroups, which were used to compare neurogenesis marker expression. Results Out of >60,000 genes, the most significantly differentially expressed gene in schizophrenia was CD163, a macrophage marker, which was increased 3.3 times compared to controls and confirmed by qPCR. Abundant CD163+ macrophages were located surrounding blood vessels, in the parenchyma and seem to infiltrate throughout the SEZ where neural stem and progenitor cells typically reside. Macrophage cell density was increased in schizophrenia compared to controls and bipolar disorder (by 29% and 61%; p = 0.017 and p = 0.002 respectively). CD163 expression positively correlated with the quiescent neural stem cell marker GFAPδ (r = 0.56, p = 0.001), and negatively correlated with neuronal progenitor marker ASCL1 (r = - 0.40, p = 0.032) in schizophrenia but not bipolar disorder. Cluster analysis of inflammatory gene expression revealed 40% of schizophrenia but only 10% of control cases were highly inflamed. The high inflammation schizophrenia subgroup had increased CD163 and GFAPδ expression but decreased ASCL1 expression (all p < 0.026). Discussion Increased macrophages in the SEZ is a key difference in schizophrenia pathology and potentially drives heightened inflammation in a subgroup. Inflammation has varied effects on different stages of neurogenesis in schizophrenia but not bipolar disorder, implicating divergent mechanisms leading to reduced neurogenesis in each psychiatric condition. In schizophrenia, macrophages and high inflammation seem to reduce neuronal differentiation and sustain neural stem cell quiescence, likely blunting stem cell proliferation. Therefore, reduced SEZ neurogenesis across the lifespan in schizophrenia may contribute to the widely reported inhibitory interneuron deficits.
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Reduction in IGF1 mRNA in the Human Subependymal Zone During Aging
Aging and disease, 2019Co-Authors: Christin Weissleder, Kl Double, Guy Barry, Samantha J. Fung, Matthew Wong, Maree J. Webster, Cs WeickertAbstract:The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the Subependymal Zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ.
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Reduction in IGF1 mRNA in the human Subependymal Zone during aging
'Aging and Disease', 2019Co-Authors: Weissleder C, Barry G, Sj Fung, Mw Wong, Kl Double, Mj Webster, Cs WeickertAbstract:© 2018 Weissleder C et al. The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the Subependymal Zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ
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Dataset for: Early life decline in neurogenesis markers and age-related changes of TrkB splice variant expression in the human Subependymal Zone
2017Co-Authors: Christin Weissleder, Samantha J. Fung, Joel E. Kleinman, Glenda M. Halliday, Chunhui Yang, Debora A. Rothmond, Mari A Kondo, Matthew W Wong, Maree Webster, Cs WeickertAbstract:Neurogenesis in the Subependymal Zone (SEZ) declines across the human lifespan and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about Subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n=26-35, 41 days–43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into aging (n=50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into aging, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ
Christin Weissleder - One of the best experts on this subject based on the ideXlab platform.
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Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder.
Schizophrenia bulletin, 2020Co-Authors: Christin Weissleder, Guy Barry, Maree J. Webster, Cs WeickertAbstract:The generation of inhibitory interneurons from neural stem cells in the Subependymal Zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the Subependymal Zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.
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O11.5. INCREASED INFLAMMATION AND MACROPHAGE INFILTRATION IS ASSOCIATED WITH ALTERED Subependymal Zone NEUROGENESIS IN SCHIZOPHRENIA BUT NOT BIPOLAR DISORDER
Schizophrenia Bulletin, 2020Co-Authors: Hayley North, Christin Weissleder, Guy Barry, Maree J. Webster, Mainá Bitar, Janice M. Fullerton, Rachel Sager, Cs WeickertAbstract:Abstract Background Inflammation is implicated in the pathogenesis of schizophrenia and bipolar disorder. Inflammation regulates neurogenesis, and markers for stem cells and neuronal progenitors are reduced in schizophrenia and bipolar disorder in the Subependymal Zone (SEZ) – the brain’s largest region of neurogenesis. This research aimed to discover core differences in gene expression and cellular composition in the SEZ in psychiatric disorders that may contribute to dysregulated neurogenesis. Methods We performed total RNA sequencing in the SEZ of 20 post-mortem schizophrenia and 21 control brains. Quantitative PCR (qPCR) and immunohistochemistry were performed in 32 schizophrenia and 32 control overlapping cases and 29 bipolar disorder cases. Immunohistochemistry was used for quantification and localisation of CD163+ macrophages. Cluster-analysis of IL6, IL6R, IL1R1 and SERPINA3 expression defined low and high inflammation subgroups, which were used to compare neurogenesis marker expression. Results Out of >60,000 genes, the most significantly differentially expressed gene in schizophrenia was CD163, a macrophage marker, which was increased 3.3 times compared to controls and confirmed by qPCR. Abundant CD163+ macrophages were located surrounding blood vessels, in the parenchyma and seem to infiltrate throughout the SEZ where neural stem and progenitor cells typically reside. Macrophage cell density was increased in schizophrenia compared to controls and bipolar disorder (by 29% and 61%; p = 0.017 and p = 0.002 respectively). CD163 expression positively correlated with the quiescent neural stem cell marker GFAPδ (r = 0.56, p = 0.001), and negatively correlated with neuronal progenitor marker ASCL1 (r = - 0.40, p = 0.032) in schizophrenia but not bipolar disorder. Cluster analysis of inflammatory gene expression revealed 40% of schizophrenia but only 10% of control cases were highly inflamed. The high inflammation schizophrenia subgroup had increased CD163 and GFAPδ expression but decreased ASCL1 expression (all p < 0.026). Discussion Increased macrophages in the SEZ is a key difference in schizophrenia pathology and potentially drives heightened inflammation in a subgroup. Inflammation has varied effects on different stages of neurogenesis in schizophrenia but not bipolar disorder, implicating divergent mechanisms leading to reduced neurogenesis in each psychiatric condition. In schizophrenia, macrophages and high inflammation seem to reduce neuronal differentiation and sustain neural stem cell quiescence, likely blunting stem cell proliferation. Therefore, reduced SEZ neurogenesis across the lifespan in schizophrenia may contribute to the widely reported inhibitory interneuron deficits.
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Reduction in IGF1 mRNA in the Human Subependymal Zone During Aging
Aging and disease, 2019Co-Authors: Christin Weissleder, Kl Double, Guy Barry, Samantha J. Fung, Matthew Wong, Maree J. Webster, Cs WeickertAbstract:The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the Subependymal Zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ.
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Early life decline in neurogenesis markers and age-related changes of TrkB splice variant expression in the human Subependymal Zone
The European journal of neuroscience, 2017Co-Authors: Christin Weissleder, Samantha J. Fung, Matthew Wong, Mary M. Herman, Joel E. Kleinman, Glenda M. Halliday, Mari Kondo, Chunhui Yang, Debora A. Rothmond, Maree J. WebsterAbstract:Neurogenesis in the Subependymal Zone (SEZ) declines across the human lifespan and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about Subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n=26-35, 41 days–43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into aging (n=50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into aging, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ. This article is protected by copyright. All rights reserved.
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Dataset for: Early life decline in neurogenesis markers and age-related changes of TrkB splice variant expression in the human Subependymal Zone
2017Co-Authors: Christin Weissleder, Samantha J. Fung, Joel E. Kleinman, Glenda M. Halliday, Chunhui Yang, Debora A. Rothmond, Mari A Kondo, Matthew W Wong, Maree Webster, Cs WeickertAbstract:Neurogenesis in the Subependymal Zone (SEZ) declines across the human lifespan and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about Subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n=26-35, 41 days–43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into aging (n=50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into aging, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ
Maree J. Webster - One of the best experts on this subject based on the ideXlab platform.
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Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder.
Schizophrenia bulletin, 2020Co-Authors: Christin Weissleder, Guy Barry, Maree J. Webster, Cs WeickertAbstract:The generation of inhibitory interneurons from neural stem cells in the Subependymal Zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the Subependymal Zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.
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O11.5. INCREASED INFLAMMATION AND MACROPHAGE INFILTRATION IS ASSOCIATED WITH ALTERED Subependymal Zone NEUROGENESIS IN SCHIZOPHRENIA BUT NOT BIPOLAR DISORDER
Schizophrenia Bulletin, 2020Co-Authors: Hayley North, Christin Weissleder, Guy Barry, Maree J. Webster, Mainá Bitar, Janice M. Fullerton, Rachel Sager, Cs WeickertAbstract:Abstract Background Inflammation is implicated in the pathogenesis of schizophrenia and bipolar disorder. Inflammation regulates neurogenesis, and markers for stem cells and neuronal progenitors are reduced in schizophrenia and bipolar disorder in the Subependymal Zone (SEZ) – the brain’s largest region of neurogenesis. This research aimed to discover core differences in gene expression and cellular composition in the SEZ in psychiatric disorders that may contribute to dysregulated neurogenesis. Methods We performed total RNA sequencing in the SEZ of 20 post-mortem schizophrenia and 21 control brains. Quantitative PCR (qPCR) and immunohistochemistry were performed in 32 schizophrenia and 32 control overlapping cases and 29 bipolar disorder cases. Immunohistochemistry was used for quantification and localisation of CD163+ macrophages. Cluster-analysis of IL6, IL6R, IL1R1 and SERPINA3 expression defined low and high inflammation subgroups, which were used to compare neurogenesis marker expression. Results Out of >60,000 genes, the most significantly differentially expressed gene in schizophrenia was CD163, a macrophage marker, which was increased 3.3 times compared to controls and confirmed by qPCR. Abundant CD163+ macrophages were located surrounding blood vessels, in the parenchyma and seem to infiltrate throughout the SEZ where neural stem and progenitor cells typically reside. Macrophage cell density was increased in schizophrenia compared to controls and bipolar disorder (by 29% and 61%; p = 0.017 and p = 0.002 respectively). CD163 expression positively correlated with the quiescent neural stem cell marker GFAPδ (r = 0.56, p = 0.001), and negatively correlated with neuronal progenitor marker ASCL1 (r = - 0.40, p = 0.032) in schizophrenia but not bipolar disorder. Cluster analysis of inflammatory gene expression revealed 40% of schizophrenia but only 10% of control cases were highly inflamed. The high inflammation schizophrenia subgroup had increased CD163 and GFAPδ expression but decreased ASCL1 expression (all p < 0.026). Discussion Increased macrophages in the SEZ is a key difference in schizophrenia pathology and potentially drives heightened inflammation in a subgroup. Inflammation has varied effects on different stages of neurogenesis in schizophrenia but not bipolar disorder, implicating divergent mechanisms leading to reduced neurogenesis in each psychiatric condition. In schizophrenia, macrophages and high inflammation seem to reduce neuronal differentiation and sustain neural stem cell quiescence, likely blunting stem cell proliferation. Therefore, reduced SEZ neurogenesis across the lifespan in schizophrenia may contribute to the widely reported inhibitory interneuron deficits.
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Reduction in IGF1 mRNA in the Human Subependymal Zone During Aging
Aging and disease, 2019Co-Authors: Christin Weissleder, Kl Double, Guy Barry, Samantha J. Fung, Matthew Wong, Maree J. Webster, Cs WeickertAbstract:The cell proliferation marker, Ki67 and the immature neuron marker, doublecortin are both expressed in the major human neurogenic niche, the Subependymal Zone (SEZ), but expression progressively decreases across the adult lifespan (PMID: 27932973). In contrast, transcript levels of several mitogens (transforming growth factor α, epidermal growth factor and fibroblast growth factor 2) do not decline with age in the human SEZ, suggesting that other growth factors may contribute to the reduced neurogenic potential. While insulin like growth factor 1 (IGF1) regulates neurogenesis throughout aging in the mouse brain, the extent to which IGF1 and IGF family members change with age and relate to adult neurogenesis markers in the human SEZ has not yet been determined. We used quantitative polymerase chain reaction to examine gene expression of seven IGF family members [IGF1, IGF1 receptor, insulin receptor and high-affinity IGF binding proteins (IGFBPs) 2, 3, 4 and 5] in the human SEZ across the adult lifespan (n=50, 21-103 years). We found that only IGF1 expression significantly decreased with increasing age. IGFBP2 and IGFBP4 expression positively correlated with Ki67 mRNA. IGF1 expression positively correlated with doublecortin mRNA, whereas IGFBP2 expression negatively correlated with doublecortin mRNA. Our results suggest IGF family members are local regulators of neurogenesis and indicate that the age-related reduction in IGF1 mRNA may limit new neuron production by restricting neuronal differentiation in the human SEZ.
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Early life decline in neurogenesis markers and age-related changes of TrkB splice variant expression in the human Subependymal Zone
The European journal of neuroscience, 2017Co-Authors: Christin Weissleder, Samantha J. Fung, Matthew Wong, Mary M. Herman, Joel E. Kleinman, Glenda M. Halliday, Mari Kondo, Chunhui Yang, Debora A. Rothmond, Maree J. WebsterAbstract:Neurogenesis in the Subependymal Zone (SEZ) declines across the human lifespan and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about Subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n=26-35, 41 days–43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into aging (n=50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into aging, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ. This article is protected by copyright. All rights reserved.
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Decline in Proliferation and Immature Neuron Markers in the Human Subependymal Zone during Aging: Relationship to EGF- and FGF-Related Transcripts.
Frontiers in aging neuroscience, 2016Co-Authors: Christin Weissleder, Kl Double, Guy Barry, Samantha J. Fung, Matthew Wong, Maree J. Webster, Glenda M. Halliday, Cs WeickertAbstract:Neuroblasts exist within the human Subependymal Zone (SEZ); however, it is debated to what extent neurogenesis changes during normal aging. It is also unknown how precursor proliferation may correlate with the generation of neuronal and glial cells or how expression of growth factors and receptors may change throughout the adult lifespan. We provided evidence of dividing cells in the human SEZ in conjunction with a dramatic age-related decline (n=50; 21-103 years) of mRNAs indicative of proliferating cells (Ki67) and immature neurons (doublecortin). Microglia mRNA (ionized calcium-binding adapter molecule 1) increased during aging, whereas transcript levels of stem/precursor cells (glial fibrillary acidic protein delta and achaete-scute homolog 1), astrocytes (vimentin and glial fibrillary acidic protein) and oligodendrocytes (oligodendrocyte lineage transcription factor 2) remained stable. Epidermal growth factor receptor (EGFR) and fibroblast growth factor 2 (FGF2) mRNAs increased throughout adulthood, while transforming growth factor alpha (TGFα), EGF, Erb-B2 receptor tyrosine kinase 4 (ErbB4) and FGF receptor 1 (FGFR1) mRNAs were unchanged across adulthood. Cell proliferation mRNA positively correlated with FGFR1 transcripts. Immature neuron and oligodendrocyte expression positively correlated with TGFα and ErbB4 mRNAs, whilst astrocyte transcripts positively correlated with EGF, FGF2 and FGFR1 mRNAs. Microglia mRNA positively correlated with EGF and FGF2 expression. Our findings indicate that neurogenesis in the human SEZ continues well into adulthood, although proliferation and neuronal differentiation may decline across adulthood. We suggest that mRNA expression of EGF- and FGF-related family members do not become limited during aging and may modulate neuronal and glial fate determination in the SEZ throughout human life.
Francesca Ciccolini - One of the best experts on this subject based on the ideXlab platform.
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γ-Aminobutyric A Receptor (GABAAR) Regulates Aquaporin 4 Expression in the Subependymal Zone RELEVANCE TO NEURAL PRECURSORS AND WATER EXCHANGE
The Journal of biological chemistry, 2014Co-Authors: Udo Schmidt-edelkraut, Fabian Poetz, Ilaria Oliva, Claudia Mandl, Gabriele Hölzl-wenig, Kai Schönig, Dusan Bartsch, Francesca CiccoliniAbstract:Activation of γ-aminobutyric A receptors (GABAARs) in the Subependymal Zone (SEZ) induces hyperpolarization and osmotic swelling in precursors, thereby promoting surface expression of the epidermal growth factor receptor (EGFR) and cell cycle entry. However, the mechanisms underlying the GABAergic modulation of cell swelling are unclear. Here, we show that GABAARs colocalize with the water channel aquaporin (AQP) 4 in prominin-1 immunopositive (P+) precursors in the postnatal SEZ, which include neural stem cells. GABAAR signaling promotes AQP4 expression by decreasing serine phosphorylation associated with the water channel. The modulation of AQP4 expression by GABAAR signaling is key to its effect on cell swelling and EGFR expression. In addition, GABAAR function also affects the ability of neural precursors to swell in response to an osmotic challenge in vitro and in vivo. Thus, the regulation of AQP4 by GABAARs is involved in controlling activation of neural stem cells and water exchange dynamics in the SEZ.
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expression of tlx in both stem cells and transit amplifying progenitors regulates stem cell activation and differentiation in the neonatal lateral Subependymal Zone
Stem Cells, 2011Co-Authors: Kirsten Obernier, Claudia Mandl, Ina K Simeonova, Tatiana Fila, Gabriele Holzlwenig, Paula Monaghannichols, Francesca CiccoliniAbstract:Niche homeostasis in the postnatal Subependymal Zone of the lateral ventricle (lSEZ) requires coordinated proliferation and differentiation of neural progenitor cells. The mechanisms regulating this balance are scarcely known. Recent observations indicate that the orphan nuclear receptor Tlx is an intrinsic factor essential in maintaining this balance. However, the effect of Tlx on gene expression depends on age and cell-type cues. Therefore, it is essential to establish its expression pattern at different developmental ages. Here, we show for the first time that in the neonatal lSEZ activated neural stem cells (NSCs) and especially transit-amplifying progenitors (TAPs) express Tlx and that its expression may be regulated at the posttranscriptional level. We also provide evidence that in both cell types Tlx affects gene expression in a positive and negative manner. In activated NSCs, but not in TAPs, absence of Tlx leads to overexpression of negative cell cycle regulators and impairment of proliferation. Moreover, in both cell types, the homeobox transcription factor Dlx2 is downregulated in the absence of Tlx. This is paralleled by increased expression of Olig2 in activated NSCs and glial fibrillary acidic protein in TAPs, indicating that in both populations Tlx decreases gliogenesis. Consistent with this, we found a higher proportion of cells expressing glial makers in the neonatal lSEZ of mutant mice than in the wild type counterpart. Thus, Tlx playing a dual role affects the expression of distinct genes in these two lSEZ cell types. STEM CELLS 2011; 29:1415–1426
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Expression of Tlx in Both Stem Cells and Transit Amplifying Progenitors Regulates Stem Cell Activation and Differentiation in the Neonatal Lateral Subependymal Zone
Stem cells (Dayton Ohio), 2011Co-Authors: Kirsten Obernier, Claudia Mandl, Gabriele Hölzl-wenig, Ina K Simeonova, Tatiana Fila, Paula Monaghan-nichols, Francesca CiccoliniAbstract:Niche homeostasis in the postnatal Subependymal Zone of the lateral ventricle (lSEZ) requires coordinated proliferation and differentiation of neural progenitor cells. The mechanisms regulating this balance are scarcely known. Recent observations indicate that the orphan nuclear receptor Tlx is an intrinsic factor essential in maintaining this balance. However, the effect of Tlx on gene expression depends on age and cell-type cues. Therefore, it is essential to establish its expression pattern at different developmental ages. Here, we show for the first time that in the neonatal lSEZ activated neural stem cells (NSCs) and especially transit-amplifying progenitors (TAPs) express Tlx and that its expression may be regulated at the posttranscriptional level. We also provide evidence that in both cell types Tlx affects gene expression in a positive and negative manner. In activated NSCs, but not in TAPs, absence of Tlx leads to overexpression of negative cell cycle regulators and impairment of proliferation. Moreover, in both cell types, the homeobox transcription factor Dlx2 is downregulated in the absence of Tlx. This is paralleled by increased expression of Olig2 in activated NSCs and glial fibrillary acidic protein in TAPs, indicating that in both populations Tlx decreases gliogenesis. Consistent with this, we found a higher proportion of cells expressing glial makers in the neonatal lSEZ of mutant mice than in the wild type counterpart. Thus, Tlx playing a dual role affects the expression of distinct genes in these two lSEZ cell types.
