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Subventricular Zone (subventricular + zone)
Selected AbstractsLithium Restores Neurogenesis in the Subventricular Zone of the Ts65Dn Mouse, a Model for Down SyndromeBRAIN PATHOLOGY, Issue 1 2010Patrizia Bianchi Abstract Down syndrome (DS), a high-incidence genetic pathology, involves brain hypoplasia and mental retardation. Emerging evidence suggests that reduced neurogenesis may be a major determinant of brain underdevelopment in DS. To establish whether it is possible to improve neurogenesis in DS, Ts65Dn mice,the most widely used model for DS,and euploid mice were treated with control or lithium chow for 1 month. During the last 3 days animals received one daily injection of 5-bromo-2-deoxyuridine (BrdU),a marker of proliferating cells,and were sacrificed 24 h after the last injection. Neurogenesis was examined in the subventricular zone (SVZ), a region that retains a neurogenic potential across life. We found that Ts65Dn mice had less (,40%) BrdU+ cells than euploid mice, indicating severe proliferation impairment. Treatment with lithium increased the number of Brdu+ cells in both euploid and Ts65Dn mice. In the latter the number of Brdu+ cells became similar to that of untreated euploid mice. Our study shows that lithium is able to restore cell proliferation in the SVZ of the Ts65Dn mouse and point at treatments with mood stabilizers as a potential tool to improve neurogenesis in patients with DS. [source] The expression of Scratch genes in the developing and adult brainDEVELOPMENTAL DYNAMICS, Issue 9 2006Faustino Marín Abstract The Scratch genes belong to the Snail superfamily of zinc-finger transcription factors present in the metazoa, represented in mammals by the Scratch1 and Scratch2 genes. We have analyzed the expression of these genes in the brain of mice at developmental stages between 9.5 days-post-coitum to adulthood. Both genes are expressed in the mantle layer of the neuroepithelium at mid-gestational stages in all regions except for the region corresponding to the V2 interneuron column, which lacked Scratch2 transcripts. From perinatal to adult stages, the expression patterns of the two genes differ. Scratch1 remains strongly expressed in almost all brain regions, although it is not found in some ventral structures such as motor nuclei and hypothalamic regions. In contrast, Scratch2 expression progressively diminishes and virtually no expression can be detected in the adult brain. Nevertheless, strong expression of Scratch2 is retained in the postnatal cortical subventricular zone, in the inner part of the cerebellar external granular layer, and in the glial cells of the adult vomeronasal nerve. Developmental Dynamoics 235:2586,2591, 2006. © 2006 Wiley-Liss, Inc. [source] Polysialic acid regulates cell contact-dependent neuronal differentiation of progenitor cells from the subventricular zoneDEVELOPMENTAL DYNAMICS, Issue 4 2004Athanasios K. Petridis Abstract Expression of polysialic acid (PSA) promotes migration of progenitor cells from the subventricular zone (SVZ) to the olfactory bulb, where they differentiate into interneurons. This differentiation has been found to coincide with a loss of PSA. Moreover, specific removal of PSA from the mouse SVZ by endoneuraminidase-N was found to cause premature differentiation, as evidenced by neurite outgrowth and tyrosine hydroxylase synthesis in vivo and by expression of neurofilament-L and ,III-tubulin in SVZ explant cultures. This differentiation involved activation of mitogen-activated protein kinase through p59fyn and was blocked by its inhibition. The effects of PSA removal were found to be cell contact-dependent and to be reduced by anti,neural cell adhesion molecule antibodies. These findings indicate that PSA expression regulates the fate of SVZ precursors by two contact-dependent mechanisms, the previously reported reduction in cell,cell adhesion that allows cell translocation, and the postponement of cell differentiation that otherwise would be induced by signals generated through surface molecule-mediated cell,cell interactions. Developmental Dynamics 230:675,684, 2004. © 2004 Wiley-Liss, Inc. [source] The rho GTPase Rac1 is required for proliferation and survival of progenitors in the developing forebrainDEVELOPMENTAL NEUROBIOLOGY, Issue 9 2010Dino P. Leone Abstract Progenitor cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing forebrain give rise to neurons and glial cells, and are characterized by distinct morphologies and proliferative behaviors. The mechanisms that distinguish VZ and SVZ progenitors are not well understood, although the homeodomain transcription factor Cux2 and Cyclin D2, a core component of the cell cycle machinery, are specifically involved in controlling SVZ cell proliferation. Rho GTPases have been implicated in regulating the proliferation, differentiation, and migration of many cell types, and one family member, Cdc42, affects the polarity and proliferation of radial glial cells in the VZ. Here, we show that another family member, Rac1, is required for the normal proliferation and differentiation of SVZ progenitors and for survival of both VZ and SVZ progenitors. A forebrain-specific loss of Rac1 leads to an SVZ-specific reduction in proliferation, a concomitant increase in cell cycle exit, and premature differentiation. In Rac1 mutants, the SVZ and VZ can no longer be delineated, but rather fuse to become a single compact zone of intermingled cells. Cyclin D2 expression, which is normally expressed by both VZ and SVZ progenitors, is reduced in Rac1 mutants, suggesting that the mutant cells differentiate precociously. Rac1-deficient mice can still generate SVZ-derived upper layer neurons, indicating that Rac1 is not required for the acquisition of upper layer neuronal fates, but instead is needed for the normal regulation of proliferation by progenitor cells in the SVZ. © 2010 Wiley Periodicals, Inc. Develop Neurobiol 70: 659,678, 2010 [source] Species-specific injury-induced cell proliferation in the hippocampus and subventricular zone of food-storing and nonstoring wild birdsDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2010L.M. Law Abstract Cells are continuously born and incorporated into the adult hippocampus (HP). Adult neurogenesis might act to increase the total number of cells or replace dead cells. Thus, neurogenesis might be a primary factor in augmenting, maintaining, or even recovering functions. In zebra finches, HP injury increases cell proliferation in the HP and stem cell rich subventricular zone (SVZ). It is unknown what effect injury has on a species dependent upon the HP for survival in the wild. In food-storing birds, recovery of caches is seasonal, necessary for survival, dependent upon the HP and is concomitant with a peak in HP neurogenesis. During the fall, food-storing black-capped chickadees (BCCs) and nonstoring dark-eyed juncos (DEJs) were captured and given a unilateral penetrating lesion to the HP one day later. On day 3, birds were injected with the mitotic marker 5-bromo-2,-deoxyuridine (BrdU) and perfused on day 10. If unlesioned, more BrdU-labeled cells were observed in the HP and SVZ of BCCs compared to DEJs, indicating higher innate cell proliferation or incorporation in BCCs. If lesioned, BrdU-labeled cells increased in the injured HP of both species; however, lesions caused larger increases in DEJs. DEJs also showed increases in BrdU-labeled cells in the SVZ and contralateral HP. BCCs showed no such increases on day 10. Thus, during the fall food-storing season, storers showed suppressed injury-induced cell proliferation and/or reduced survival rates of these new cells compared to nonstorers. These species differences may provide a useful model for isolating factors involved in cellular responses following injury. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2010 [source] Gap junctions are involved in cell migration in the early postnatal subventricular zoneDEVELOPMENTAL NEUROBIOLOGY, Issue 11 2009Mônica Marins Abstract The massive migration of neuroblasts and young neurons through the anterior extension of the postnatal subventricular zone (SVZ), known as the rostral migratory stream (RMS) is still poorly understood on its molecular basis. In this work, we investigated the involvement of gap junctional communication (GJC) in the robust centrifugal migration from SVZ/RMS explants obtained from early postnatal (P4) rats. Cells were dye-coupled in homocellular and heterocellular pairings and expressed at least two connexins, Cx 43 and 45. Treatment with the uncoupler agent carbenoxolone (CBX, 10,100 ,M) reversibly reduced outgrowth from SVZ explants, while its inactive analog, glycyrhizinic acid (GZA), had no effect. Consistent with a direct effect on cell migration, time-lapse video microscopy show that different pharmacological uncouplers cause an abrupt and reversible arrest of cell movement in explants. Our results indicate that GJC is positively involved in the migration of neuroblasts within the SVZ/RMS. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009 [source] Polysialic acid controls NCAM-induced differentiation of neuronal precursors into calretinin-positive olfactory bulb interneuronsDEVELOPMENTAL NEUROBIOLOGY, Issue 9 2008Iris Röckle Abstract Understanding the mechanisms that regulate neurogenesis is a prerequisite for brain repair approaches based on neuronal precursor cells. One important regulator of postnatal neurogenesis is polysialic acid (polySia), a post-translational modification of the neural cell adhesion molecule NCAM. In the present study, we investigated the role of polySia in differentiation of neuronal precursors isolated from the subventricular zone of early postnatal mice. Removal of polySia promoted neurite induction and selectively enhanced maturation into a calretinin-positive phenotype. Expression of calbindin and Pax6, indicative for other lineages of olfactory bulb interneurons, were not affected. A decrease in the number of TUNEL-positive cells indicated that cell survival was slightly improved by removing polySia. Time lapse imaging revealed the absence of chain migration and low cell motility, in the presence and absence of polySia. The changes in survival and differentiation, therefore, could be dissected from the well-known function of polySia as a promoter of precursor migration. The differentiation response was mimicked by exposure of cells to soluble or substrate-bound NCAM and prevented by the C3d-peptide, a synthetic ligand blocking NCAM interactions. Moreover, a higher degree of differentiation was observed in cultures from polysialyltransferase-depleted mice and after NCAM exposure of precursors from NCAM-knockout mice demonstrating that the NCAM function is mediated via heterophilic binding partners. In conclusion, these data reveal that polySia controls instructive NCAM signals, which direct the differentiation of subventricular zone-derived precursors towards the calretinin-positive phenotype of olfactory bulb interneurons. © 2008 Wiley Periodicals, Inc. Develop Neurobiol, 2008 [source] The effects of social environment on adult neurogenesis in the female prairie voleDEVELOPMENTAL NEUROBIOLOGY, Issue 2 2002Christie D. Fowler Abstract In the mammalian brain, adult neurogenesis has been found to occur primarily in the subventricular zone (SVZ) and dentate gyrus of the hippocampus (DG) and to be influenced by both exogenous and endogenous factors. In the present study, we examined the effects of male exposure or social isolation on neurogenesis in adult female prairie voles (Microtus ochrogaster). Newly proliferated cells labeled by a cell proliferation marker, 5-bromo-2,-deoxyuridine (BrdU), were found in the SVZ and DG, as well as in other brain areas, such as the amygdala, hypothalamus, neocortex, and caudate/putamen. Two days of male exposure significantly increased the number of BrdU-labeled cells in the amygdala and hypothalamus in comparison to social isolation. Three weeks later, group differences in BrdU labeling generally persisted in the amygdala, whereas in the hypothalamus, the male-exposed animals had more BrdU-labeled cells than did the female-exposed animals. In the SVZ, 2 days of social isolation increased the number of BrdU-labeled cells compared to female exposure, but this difference was no longer present 3 weeks later. We have also found that the vast majority of the BrdU-labeled cells contained a neuronal marker, indicating neuronal phenotypes. Finally, group differences in the number of cells undergoing apoptosis were subtle and did not seem to account for the observed differences in BrdU labeling. Together, our data indicate that social environment affects neuron proliferation in a stimulus- and site-specific manner in adult female prairie voles. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 115,128, 2002 [source] Extracerebellar progenitors grafted to the neurogenic milieu of the postnatal rat cerebellum adapt to the host environment but fail to acquire cerebellar identitiesEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2010Chiara Rolando Abstract Stem or progenitor cells acquire specific regional identities during early ontogenesis. Nonetheless, there is evidence that cells heterotopically transplanted to neurogenic regions of the developing or mature central nervous system may switch their fate to adopt host-specific phenotypes. Here, we isolated progenitor cells from different germinative sites along the neuraxis where GABAergic interneurons are produced (telencephalic subventricular zone, medial ganglionic eminence, ventral mesencephalon and dorsal spinal cord), and grafted them to the prospective white matter of the postnatal rat cerebellum, at the time when local interneurons are generated. The phenotype acquired by transplanted cells was assessed by different criteria, including expression of region-specific transcription factors, acquisition of morphological and neurochemical traits, and integration in the cerebellar cytoarchitecture. Regardless of their origin, all the different types of donor cells engrafted in the cerebellar parenchyma and developed mature neurons that shared some morphological and neurochemical features with local inhibitory interneurons, particularly in the deep nuclei. Nevertheless, transplanted cells failed to activate cerebellar-specific regulatory genes. In addition, their major structural features, the expression profiles of type-specific markers and the laminar placement in the recipient cortex did not match those of endogenous interneurons generated during the same developmental period. Therefore, although exogenous cells are influenced by the cerebellar milieu and show remarkable capabilities for adapting to the foreign environment, they essentially fail to switch their fate, integrate in the host neurogenic mechanisms and adopt clear-cut cerebellar identities. [source] Expression of Sox11 in adult neurogenic niches suggests a stage-specific role in adult neurogenesisEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2009Anja Haslinger Abstract In the mammalian brain, neural stem and progenitor cells in the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus generate new neurons throughout adulthood. The generation of new functional neurons is a complex process that is tightly controlled by extrinsic signals and that is characterized by stage-specific gene expression programs and cell biological processes. The transcription factors regulating such stage-specific developmental steps in adult neurogenesis are largely unknown. Here we report that Sox11, a member of the group C Sox transcription factor family, is prominently expressed in the neurogenic areas of the adult brain. Further analysis revealed that Sox11 expression is strictly confined to doublecortin-expressing neuronally committed precursors and immature neurons but that Sox11 is not expressed in non-committed Sox2-expressing precursor cells and mature neurons of the adult neurogenic lineage. Finally, overexpression of Sox11 promotes the generation of doublecortin-positive immature neurons from adult neural stem cells in vitro. These data indicate that Sox11 is involved in the transcriptional regulation of specific gene expression programs in adult neurogenesis at the stage of the immature neuron. [source] Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synucleinEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2009Franz Marxreiter Abstract In familial and sporadic forms of Parkinson's disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies. [source] Generation recruitment and death of brain cells throughout the life cycle of Sorex shrews (Lipotyphla)EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2008Katarzyna Bartkowska Abstract Young shrews of the genus Sorex that are born in early summer reduce their body size before wintering, including a reduction of brain weight of 10,30%. In the spring they mature sexually, double their body weight and regain about half of the loss in brain weight. To investigate the mechanisms of brain weight oscillations we studied the rate of cell death and generation in the brain during the whole life cycle of the common shrew (Sorex araneus) and pygmy shrew (S. minutus). After weaning, shrews generate new brain cells in only two mammalian neurogenic zones and approximately 80% of these develop into neurones. The increase of the shrew brain weight in the spring did not depend on recruitment of new cells. Moreover, adult Sorex shrews did not generate new cells in the dentate gyri. Injections of 5-HT1A receptor agonists in the adult shrews induced neurogenesis in their dentate gyri, showing the presence of dormant progenitor cells. Generation of new neurones in the subventricular zone of the lateral ventricles and their recruitment to olfactory bulbs continued throughout life. TUNEL labelling showed that the rate of cell death in all brain structures, including the proliferation zones and olfactory bulb, was very low throughout life. We conclude that neither cell death nor recruitment significantly contributes to seasonal oscillations and the net loss of brain weight in the Sorex shrews. With the exception of dentate gyrus and olfactory bulb, cellular populations of brain structures are stable throughout the life cycle of these shrews. [source] Recruiting new neurons from the subventricular zone to the rat postnatal cortex: an organotypic slice culture modelEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2008A. G. Dayer Abstract The neurogenic subventricular zone (SVZ) of the lateral ventricle is a potential source for neuronal replacement in the postnatal or adult neocortex after injury. Here we present a novel model system to directly explore the cellular mechanisms of this process. In order to visualize directed migration from the SVZ towards the cortex, we transplanted green fluorescent protein-labeled progenitor/stem cells into the SVZ of newborn rats. At 2 days after transplantation, we generated organotypic slice cultures and applied fluorescent time-lapse imaging to explore directly the migration and integration of donor cells into the host tissue for up to 2 weeks. Our studies revealed that subventricular grafts provide a significant number of immature neurons to neocortical regions. In the cortex, immature neurons first migrate radially towards the pial surface and then differentiate into GABAergic interneurons. We conclude that our model system presents a novel and effective experimental paradigm to evaluate the recruitment of SVZ-derived neurons into the postnatal cortex, a phenomenon that may represent a potential route for cortical repair. [source] Depolarization promotes GAD 65-mediated GABA synthesis by a post-translational mechanism in neural stem cell-derived neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2008Nidhi Gakhar-Koppole Abstract Neuronal activity regulates neurogenesis and neuronal differentiation in the mammalian brain. The commencement of neurotransmitter expression establishes the neuronal phenotype and enables the formation of functional connectivity between neurons. In addition, release of neurotransmitters from differentiating neurons may modulate the behaviour of neural precursors. Here, we show that neuronal activity regulates ,-aminobutyric acid (GABA) expression in neurons generated from stem cells of the striatum and adult subventricular zone (SVZ). Differentiating neurons display spontaneous Ca2+ events, which are voltage-gated calcium channel (VGCC) dependent. Depolarization increases both the frequency of Ca2+ transients and the amount of Ca2+ influx in differentiating neurons. We show that depolarization-dependent GABA expression is regulated by the amplitude and not by the frequency of Ca2+ influx. Brief activation of VGCCs leads to Ca2+ influx that in turn promotes a rapid expression of GABA. Depolarization-dependent GABA expression does not require changes in gene expression. Instead, it involves cAMP-dependent protein kinase (PKA) and Ca2+ and phospholipid-dependent protein kinase (PKC) signalling. Activity increases the number of glutamic acid decarboxylase (GAD) 65-immunoreactive neurons in a PKA-dependent manner, without altering the expression of GAD 65, suggesting that depolarization promotes recruitment of GAD 65 by a post-translational mechanism. In line with this, depolarization does not permanently increase the expression of GABA in neurons derived from neural stem cells of the embryonic striatum, cortex and adult SVZ. Thus, neuronal activity does not merely accelerate neuronal differentiation but it may alter the mechanism of GABA synthesis in newly generated neurons. [source] Olfactory bulb hypoplasia in Prokr2 null mice stems from defective neuronal progenitor migration and differentiationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Haydn M. Prosser Abstract New neurons are added on a daily basis to the olfactory bulb (OB) of a mammal, and this phenomenon exists throughout its lifetime. These new cells are born in the subventricular zone and migrate to the OB via the rostral migratory stream (RMS). To examine the role of the prokineticin receptor 2 (Prokr2) in neurogenesis, we created a Prokr2 null mouse, and report a decrease in the volume of its OB and also a decrease in the number of bromodeoxyuridine (BrdU)-positive cells. There is disrupted architecture of the OB, with the glomerular layer containing terminal dUTP nick-end labeling (TUNEL) -positive nuclei and also a decrease in tyrosine hydroxylase-positive neurons in this layer. In addition, there are increased numbers of doublecortin-positive neuroblasts in the RMS and increased PSA-NCAM (polysialylated form of the neural cell adhesion molecule) -positive neuronal progenitors around the olfactory ventricle, indicating their detachment from homotypic chains is compromised. Finally, in support of this, Prokr2-deficient cells expanded in vitro as neurospheres are incapable of migrating towards a source of recombinant human prokineticin 2 (PROK2). Together, these findings suggest an important role for Prokr2 in OB neurogenesis. [source] Multi-directional differentiation of doublecortin- and NG2-immunopositive progenitor cells in the adult rat neocortex in vivoEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2007Yasuhisa Tamura Abstract In the adult mammalian brain, multipotent stem or progenitor cells involved in reproduction of neurons and glial cells have been well investigated only in very restricted regions; the subventricular zone of the lateral ventricle and the dentate gyrus in the hippocampal formation. In the neocortex, a series of in vitro studies has suggested the possible existence of neural progenitor cells possessing neurogenic and/or gliogenic potential in adult mammals. However, the cellular properties of the cortical progenitor cells in vivo have not been fully elucidated. Using 5,-bromodeoxyuridine labeling and immunohistochemical analysis of cell differentiation markers, we found that a subpopulation of NG2-immunopositive cells co-expressing doublecortin (DCX), an immature neuron marker, ubiquitously reside in the adult rat neocortex. Furthermore, these cells are the major population of proliferating cells in the region. The DCX(+)/NG2(+) cells reproduced the same daughter cells, or differentiated into DCX(+)/NG2(,) (approximately 1%) or DCX(,)/NG2(+) (approximately 10%) cells within 2 weeks after cell division. The DCX(+)/NG2(,) cells were also immunopositive for TUC-4, a neuronal linage marker, suggesting that these cells were committed to neuronal cell differentiation, whereas the DCX(,)/NG2(+) cells showed faint immunoreactivity for glutathione S-transferase (GST)-pi, an oligodendrocyte lineage marker, in the cytoplasm, suggesting glial cell lineage, and thereafter the cells differentiated into NG2(,)/GST-pi(+) mature oligodendrocytes after a further 2 weeks. These findings indicate that DCX(+)/NG2(+) cells ubiquitously exist as ,multipotent progenitor cells' in the neocortex of adult rats. [source] Subventricular zone-derived neuroblast migration to the olfactory bulb is modulated by matrix remodellingEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2007Serena Bovetti Abstract In the rodent brain neural progenitor cells are born in the subventricular zone and migrate along a pathway called the rostral migratory stream (RMS) into the olfactory bulb where they differentiate into several classes of interneurones. In the adult, tangential migration in the RMS takes place in ,chains' of cells contained within glial tubes. In contrast, neonatal neuroblasts along the RMS lack these defined glial tubes and chains, migrating instead as individual cells. Time-lapse confocal microscopy of neuroblasts at each of these ages shows that individual cells migrate in a saltatory manner with bursts of high speed followed by periods of slower speed. Tangential migration within a glial tube is 20% faster than migration as individual cells. Neuroblasts may also interact and modify the extracellular matrix during migration through expression of a family of proteins, the matrix metalloproteinases (MMPs). MMPs are present and active along the subventricular zone,olfactory bulb pathway. In the presence of inhibitors of MMPs, neuroblast migration rates were reduced only when cells migrate individually. Chain migration in the adult was unaffected by MMP inhibitors. Taken together, these data suggest that MMPs only influence migration as individual cells and not as chains. [source] Characterization of TROY-expressing cells in the developing and postnatal CNS: the possible role in neuronal and glial cell developmentEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2006Tomoko Hisaoka Abstract A member of the tumor necrosis factor receptor superfamily, TROY, is expressed in the CNS of embryonic and adult mice. In the present study, we characterized TROY-expressing cells in the embryonic and postnatal forebrain. In the early embryonic forebrain, TROY was highly expressed in nestin-positive neuroepithelial cells and radial glial cells, but not in microtubule-associated protein 2-positive postmitotic neurons. During the late embryonic and postnatal development, expression of TROY was observed in radial glial cells and astrocytes, whereas its expression was not detected in neuronal lineage cells. In addition, TROY was exclusively expressed in Musashi-1-positive multipotent/glial progenitors in the postnatal subventricular zone. To investigate the functions of TROY in neural development, we overexpressed TROY in PC12 cells and established stably expressing cell clones. As expected, the signals from overexpressed TROY were constitutively transduced via the activation of the nuclear factor-,B and the c-Jun N-terminal kinase pathways in such clones. In addition, upregulation of negative basic helix,loop,helix transcription factors, HES-5 and Id2 proteins, was observed in the TROY-overexpressing clones. Interestingly, the overexpression of TROY in PC12 cells strongly inhibited nerve growth factor-induced neurite outgrowth with reduction of some markers of differentiated neurons, such as neurofilament 150 kDa and neuron-specific ,-tubulin. These findings suggest that the signaling from TROY regulates neuronal differentiation at least in part. [source] Isolation and characterization of neural precursor cells from the Sox1,GFP reporter mouseEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2005Perrine Barraud Abstract We have made use of a reporter mouse line in which enhanced green fluorescence protein (GFP) is inserted into the Sox1 locus. We show that the GFP reporter is coexpressed with the Sox1 protein as well as with other known markers for neural stem and progenitor cells, and can be used to identify and isolate these cells by fluorescence-activated cell sorting (FACS) from the developing or adult brain and from neurosphere cultures. All neurosphere-forming cells with the capacity for multipotency and self-renewal reside in the Sox1,GFP-expressing population. Thus, the Sox1,GFP reporter system is highly useful for identification, isolation and characterization of neural stem and progenitor cells, as well as for the validation of alternative means for isolating neural stem and progenitor cells. Further, transplantation experiments show that Sox1,GFP cells isolated from the foetal brain give rise to neurons and glia in vivo, and that many of the neurons display phenotypic characteristics appropriate for the developing brain region from which the Sox1,GFP precursors were derived. On the other hand, Sox1,GFP cells isolated from the adult subventricular zone or expanded neurosphere cultures gave rise almost exclusively to glial cells following transplantation. Thus, not all Sox1,GFP cells possess the same capacity for neuronal differentiation in vivo. [source] A novel role for polyamines in adult neurogenesis in rodent brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2004Jordane Malaterre Abstract Although neurogenesis in the adult is known to be regulated by various internal cues such as hormones, growth factors and cell-adherence molecules, downstream elements underlying their action at the cellular level still remain unclear. We previously showed in an insect model that polyamines (putrescine, spermidine and spermine) play specific roles in adult brain neurogenesis. Here, we demonstrate their involvement in the regulation of secondary neurogenesis in the rodent brain. Using neurosphere assays, we show that putrescine addition stimulates neural progenitor proliferation. Furthermore, in vivo depletion of putrescine by specific and irreversible inhibition of ornithine decarboxylase, the first key enzyme of the polyamine synthesis pathway, induces a consistent decrease in neural progenitor cell proliferation in the two neurogenic areas, the dentate gyrus and the subventricular zone. The present study reveals common mechanisms underlying birth of new neurons in vertebrate and invertebrate species. [source] Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulbGENES TO CELLS, Issue 10 2006Naoko Kaneko Neurogenesis in the subgranular zone of the hippocampal dentate gyrus and olfactory bulbs continues into adulthood and has been implicated in the cognitive function of the adult brain. The basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis as well as learning and memory in these regions. Herein, we report that highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive immature cells as well as neuronal nuclei (NeuN)-positive mature neurons in the dentate gyrus and olfactory bulb express multiple acetylcholine receptor subunits and make contact with cholinergic fibers. To examine the function of acetylcholine in neurogenesis, we used donepezil (Aricept), a potent and selective acetylcholinesterase inhibitor that improves cognitive impairment in Alzheimer's disease. Intraperitoneal administrations of donepezil significantly enhanced the survival of newborn neurons, but not proliferation of neural progenitor cells in the subgranular zone or the subventricular zone of normal mice. Moreover, donepezil treatment reversed the chronic stress-induced decrease in neurogenesis. Taken together, these results suggest that activation of the cholinergic system promotes survival of newborn neurons in the adult dentate gyrus and olfactory bulb under both normal and stressed conditions. [source] PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrainGLIA, Issue 16 2009M. C. Assanah Abstract Platelet-derived growth factor (PDGF) plays a major role in regulating migration, proliferation, and differentiation of glial progenitors during normal brain development and in the abnormal proliferation and dispersion that drives the formation of malignant gliomas. To further explore the relationship between PDGF's effects on normal glial progenitors and its role in the formation of gliomas, we infected progenitor cells in the subventricular zone (SVZ) of the lateral ventricle of neonatal rat pups with a retrovirus that expresses PDGF and green fluorescent protein (GFP). At 3 days post-injection (dpi), a proliferation of PDGFR,+ progenitors was seen in the SVZ and white matter around the injection site and by 10 dpi the animals had large diffusely infiltrating tumors that resembled glioblastomas. The tumors contained a massive proliferation of both infected and uninfected PDGFR,+ progenitors, suggesting that PDGF was driving tumor formation via both autocrine and paracrine signaling. Rats co-injected with two retroviruses (one that expresses PDGF-IRES-DSRED and one that expresses only GFP) formed tumors that contained a mixture of DSRED+ cells (PDGF producers) and GFP+ cells (recruited progenitors). Time-lapse microscopy of slice cultures confirmed that both DSRED+ and GFP+ cells were highly migratory and proliferative. Furthermore, adding exogenous PDGF to slice cultures generated from nontumor-bearing brains (injected with control GFP retrovirus only) stimulated the migration and proliferation of GFP+ progenitors. These findings reveal the inherent growth factor responsiveness and tumorigenic potential of PDGFR,+ progenitors and highlight the importance of paracrine signaling in stimulating glioma growth and infiltration. © 2009 Wiley-Liss, Inc. [source] An FGF-responsive astrocyte precursor isolated from the neonatal forebrainGLIA, Issue 6 2009Grace Lin Abstract Gliogenesis in the mammalian CNS continues after birth, with astrocytes being generated well into the first two postnatal weeks. In this study, we have isolated an A2B5+ astrocyte precursor (APC) from the postnatal rat forebrain, which is capable of differentiating into mature astrocytes in serum-free medium without further trophic support. Exposure to basic fibroblast growth factor (bFGF) selectively induces the APCs to proliferate, forming clusters of vimentin+ cells, which, within 2 weeks, differentiate into GFAP+ astrocytes. While bFGF functions as a potent mitogen, neither is it necessary to induce or maintain astrocyte differentiation, nor is it capable of maintaining the precursors in an immature, proliferative state. APCs exit the cell cycle and differentiate, even in the continued presence of fibroblast growth factor alone or in combination with other mitogenic factors such as platelet-derived growth factor. Under the culture conditions used, it was not possible to cause the astrocytes to re-enter cell cycle. After transplantation into the neonatal forebrain, APCs differentiated exclusively into astrocytes, regardless of brain region. Initially distributed widely within the forebrain, the precursors are most greatly concentrated within the subventricular zone (SVZ) and subcortical white matter, where they are maintained throughout postnatal development. APCs can be isolated from the SVZ and white matter of animals as late as 4 weeks after birth. © 2008 Wiley-Liss, Inc. [source] Ultrastructural and antigenic properties of neural stem cells and their progeny in adult rat subventricular zoneGLIA, Issue 2 2009Alexandre I. Danilov Abstract Neural stem cells (NSCs) in the subventricular zone (SVZ) continuously generate olfactory bulb interneurons in the adult rodent brain. Based on their ultrastructural and antigenic properties, NSCs, transient amplifying precursor cells, and neuroblasts (B, C, and A cells, respectively) have been distinguished in mouse SVZ. Here, we aimed to identify these cell types in rat SVZ ultrastructurally and at the light microscopy level, and to determine the antigenic properties of each cell type using gold and fluorescence immunolabeling. We found astrocytes with single cilia (NSCs, correspond to B cells) and neuroblasts (A cells). We also observed mitotic cells, ependymal cells, displaced ependymal cells, and mature astrocytes. In contrast, transient amplifying precursor cells (C cells) were not detected. The NSCs and neuroblasts had epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor alpha (PDGFR,) expressed on the ciliary apparatus and were the only cell types incorporating the proliferation marker BrdU. Throughout mitosis, EGFR and PDGFR, were associated with the microtubule of the mitotic spindle. Ependymal and displaced ependymal cells also expressed EGFR and PDGFR, on their cilia but did not incorporate BrdU. Our findings indicate that the NSCs in adult rat SVZ give rise directly to neuroblasts. During mitosis, the NSCs disassemble the primary cilium and symmetrically distribute EGFR and PDGFR, among their progeny. © 2008 Wiley-Liss, Inc. [source] A role for Connexin43 during neurodevelopmentGLIA, Issue 7 2007Amy E. Wiencken-Barger Abstract Connexin43 (Cx43) is the predominant gap junction protein expressed in premitotic radial glial cells and mature astrocytes. It is thought to play a role in many aspects of brain development and physiology, including intercellular communication, the release of neuroactive substances, and neural and glial proliferation and migration. To investigate the role of Cx43 in brain physiology, we generated a conditional knockout (cKO) mouse expressing Cre recombinase driven by the human GFAP promoter and a floxed Cx43 gene. The removal of Cx43 from GFAP-expressing cells affects the behavior of the mice and the development of several brain structures; however, the severity of the phenotype varies depending on the mouse background. One mouse subline, hereafter termed Shuffler, exhibits cellular disorganization of the cortex, hippocampus, and cerebellum, accompanied by ataxia and motor deficits. The Shuffler cerebellum is most affected and displays altered distribution and lamination of glia and neurons suggestive of cell migration defects. In all Shuffler mice by postnatal day two (P2), the hippocampus, cortex, and cerebellum are smaller. Disorganization of the ventricular and subventricular zone of the cortex is also evident. Given that these are sites of early progenitor cell proliferation, we suspect production and migration of neural progenitors may be altered. In conclusion, neurodevelopment of Shuffler/Cx43 cKO mice is abnormal, and the observed cellular phenotype may explain behavioral disturbances seen in these animals as well as in humans carrying Cx43 mutations. © 2007 Wiley-Liss, Inc. [source] Specific characteristic of radial glia in the human fetal telencephalonGLIA, Issue 1 2004Nada Zecevic Abstract Phenotypic characteristics of cells in the developing human telencephalic wall were analyzed using electron microscopy and immunocytochemistry with various glial and neuronal cell markers. The results suggest that multiple defined cell types emerge in the neocortical proliferative zones and are differentially regulated during embryonic development. At 5,6 weeks gestation, three major cell types are observed. Most proliferating ventricular zone (VZ) cells are labeled with radial glial (RG) markers such as vimentin, glial fibrillary acidic protein (GFAP), and glutamate astrocyte-specific transporter (GLAST) antibodies. A subpopulation of these RG cells also express the neuronal markers , III-tubulin, MAP-2, and phosphorylated neurofilament SMI-31, in addition to the stem cell marker nestin, indicating their multipotential capacity. In addition, the presence of VZ cells that immunoreact only with neuronal markers indicates the emergence of restricted neuronal progenitors. The number of multipotential progenitors in the VZ gradually decreases, whereas the number of more restricted progenitors increases systematically during the 3-month course of human corticogenesis. These results suggest that multipotential progenitors coexist with restricted neuronal progenitors and RG cells during initial corticogenesis in the human telencephalon. Since the multipotential VZ cells disappear during the major wave of neocortical neurogenesis, the RG and restricted neuronal progenitors appear to serve as the main sources of cortical neurons. Thus, the diversification of cells in human VZ and overlying subventricular zone (SVZ) begins earlier and is more pronounced than in rodents. © 2004 Wiley-Liss, Inc. [source] Proliferation of progenitor cells in the adult rat brain correlates with the presence of vimentin-expressing astrocytesGLIA, Issue 4 2001Gérard Alonso Abstract It is well established that proliferation of progenitor cells persists within the hippocampal dentate gyrus (DG) and the subventricular zone of the lateral ventricle (SVZ) in the adult brain. The aim of the present study was to determine whether the rate of cell proliferation within these germinative zones could be correlated to the occurrence of a particular glial environment. The cell proliferation marker bromodeoxyuridine (BrdU) was administrated to rats under different physiological and experimental conditions known to modify the rate of progenitor cell proliferation. Within both germinative zones, BrdU-labeled nuclei were associated with cell bodies immunostained for the neuronal marker polysialylated neural cell adhesion molecule, but not for the glial markers glial fibrillary acidic protein (GFAP) or vimentin (VIM). In all the rats examined, however, proliferating (BrdU-labeled) cells always exhibited close relationships with immature-like astrocytes that expressed both GFAP and VIM. There was a dramatic decrease of cell proliferation in the DG from both the aged rats and the corticosterone-treated adult rats that was correlated with a decreased expression of vimentin by the astrocytes present in this region. In contrast, both cell proliferation and vimentin expression were only slightly affected in the SVZ from these two treatment groups. Conversely, after either adrenalectomy or a surgical lesion through the lateral hippocampus, the increase in cell proliferation observed in the DG was correlated to the occurrence of an increased number of GFAP and VIM double immunostained structures in these regions. All together, these data suggest that immature-like astrocytes present in the germinative zones may provide a microenvironment involved in sustaining the proliferation of progenitor cells. GLIA 34:253,266, 2001. © 2001 Wiley-Liss, Inc. [source] Novel stem/progenitor cells with neuronal differentiation potential reside in the leptomeningeal nicheJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 9b 2009Francesco Bifari Abstract Stem cells capable of generating neural differentiated cells are recognized by the expression of nestin and reside in specific regions of the brain, namely, hippocampus, subventricular zone and olfactory bulb. For other brain structures, such as leptomeninges, which contribute to the correct cortex development and functions, there is no evidence so far that they may contain stem/precursor cells. In this work, we show for the first time that nestin-positive cells are present in rat leptomeninges during development up to adulthood. The newly identified nestin-positive cells can be extracted and expanded in vitro both as neurospheres, displaying high similarity with subventricular zone,derived neural stem cells, and as homogeneous cell population with stem cell features. In vitro expanded stem cell population can differentiate with high efficiency into excitable cells with neuronal phenotype and morphology. Once injected into the adult brain, these cells survive and differentiate into neurons, thus showing that their neuronal differentiation potential is operational also in vivo. In conclusion, our data provide evidence that a specific population of immature cells endowed of neuronal differentiation potential is resident in the leptomeninges throughout the life. As leptomeninges cover the entire central nervous system, these findings could have relevant implications for studies on cortical development and for regenerative medicine applied to neurological disorders. [source] Longterm quiescent cells in the aged human subventricular neurogenic system specifically express GFAP-,AGING CELL, Issue 3 2010Simone A. Van Den Berge Summary A main neurogenic niche in the adult human brain is the subventricular zone (SVZ). Recent data suggest that the progenitors that are born in the human SVZ migrate via the rostral migratory stream (RMS) towards the olfactory bulb (OB), similar to what has been observed in other mammals. A subpopulation of astrocytes in the SVZ specifically expresses an assembly-compromised isoform of the intermediate filament protein glial fibrillary acidic protein (GFAP-,). To further define the phenotype of these GFAP-, expressing cells and to determine whether these cells are present throughout the human subventricular neurogenic system, we analysed SVZ, RMS and OB sections of 14 aged brain donors (ages 74-93). GFAP-, was expressed in the SVZ along the ventricle, in the RMS and in the OB. The GFAP-, cells in the SVZ co-expressed the neural stem cell (NSC) marker nestin and the cell proliferation markers proliferating cell nuclear antigen (PCNA) and Mcm2. Furthermore, BrdU retention was found in GFAP-, positive cells in the SVZ. In the RMS, GFAP-, was expressed in the glial net surrounding the neuroblasts. In the OB, GFAP-, positive cells co-expressed PCNA. We also showed that GFAP-, cells are present in neurosphere cultures that were derived from SVZ precursors, isolated postmortem from four brain donors (ages 63-91). Taken together, our findings show that GFAP-, is expressed in an astrocytic subpopulation in the SVZ, the RMS and the OB. Importantly, we provide the first evidence that GFAP-, is specifically expressed in longterm quiescent cells in the human SVZ, which are reminiscent of NSCs. [source] Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelinationJOURNAL OF NEUROCHEMISTRY, Issue 1 2010Holly S. Cate J. Neurochem. (2010) 115, 11,22. Abstract The adult subventricular zone (SVZ) is a potential source of precursor cells to replace neural cells lost during demyelination. To better understand the molecular events that regulate neural precursor cell responsiveness in this context we undertook a microarray and quantitative PCR based analysis of genes expressed within the SVZ during cuprizone-induced demyelination. We identified an up-regulation of the genes encoding bone morphogenic protein 4 (BMP4) and its receptors. Immunohistochemistry confirmed an increase in BMP4 protein levels and also showed an increase in phosphorylated SMAD 1/5/8, a key component of BMP4 signalling, during demyelination. In vitro analysis revealed that neural precursor cells isolated from demyelinated animals, as well as those treated with BMP4, produce more astrocytes. Similarly, there were increased numbers of astrocytes in vivo within the SVZ during demyelination. Intraventricular infusion of Noggin, an endogenous antagonist of BMP4, during cuprizone-induced demyelination reduced pSMAD1/5/8, decreased astrocyte numbers and increased oligodendrocyte numbers in the SVZ. Our results suggest that lineage commitment of SVZ neural precursor cells is altered during demyelination and that BMP signalling plays a role in this process. [source] | |||||||||||||