A heterogeneous population of ependymal cells lines the brain ventricles. The evidence about the ... more A heterogeneous population of ependymal cells lines the brain ventricles. The evidence about the origin and birth dates of these cell populations is scarce. Furthermore, the possibility that mature ependymal cells are born (ependymogenesis) or self-renewed (ependymal proliferation) postnatally is controversial. The present study was designed to investigate both phenomena in wild-type (wt) and hydrocephalic α-SNAP mutant (hyh) mice at different postnatal stages. In wt mice, proliferating cells in the ventricular zone (VZ) were only found in two distinct regions: the dorsal walls of the third ventricle and Sylvian aqueduct (SA). Most proliferating cells were monociliated and nestin+, likely corresponding to radial glial cells. Postnatal cumulative BrdU-labeling showed that most daughter cells remained in the VZ of both regions and they lost nestin-immunoreactivity. Furthermore, some labeled cells became multiciliated and GLUT-1+, indicating they were ependymal cells born postnatally. Postnatal pulse BrdU-labeling and Ki-67 immunostaining further demonstrated the presence of cycling multiciliated ependymal cells. In hydrocephalic mutants, the dorsal walls of the third ventricle and SA expanded enormously and showed neither ependymal disruption nor ventriculostomies. This phenomenon was sustained by an increased ependymogenesis. Consequently, in addition to the physical and geometrical mechanisms traditionally explaining ventricular enlargement in fetal-onset hydrocephalus, we propose that postnatal ependymogenesis could also play a role. Furthermore, as generation of new ependymal cells during postnatal stages was observed in distinct regions of the ventricular walls, such as the roof of the third ventricle, it may be a key mechanism involved in the development of human type 1 interhemispheric cysts.
In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) s... more In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) stenosis and heterotopias] is poorly understood. In animal models, loss of ventricular lining (ependymal denudation) causes SA stenosis and hydrocephalus. We aimed to investigate whether ependymal denudation also takes place in human foetal SBA. Considering that ependymal denudation would be related to alterations in junction proteins, sections through SA of five SBA and six control foetuses (gestational ages ranged between 37 and 40 weeks) were immunostained for markers of ependyma (caveolin 1, βIV-tubulin, S100), junction proteins (N-cadherin, connexin-43, neural cell adhesion molecule (NCAM), blood vessels (Glut-1) and astrocytes [glial fibrillary acidic protein (GFAP)]. In control foetuses, ependymal denudation was absent. In SBA foetuses different stages of ependymal denudation were observed: (i) intact ependyma/neuroepithelium; (ii) imminent ependymal denudation (with abnormal subcellular location of junction proteins); (iii) ependymal denudation (with protrusion of neuropile into SA, formation of rosettes and macrophage invasion); (iv) astroglial reaction. It is suggested that abnormalities in the formation of gap and adherent junctions result in defective ependymal coupling, desynchronized ciliary beating and ependymal denudation, leading to hydrocephalus. The presence of various stages of ependymal denudation within the same full-term SBA foetuses suggests continuation of the process after birth.
Journal of Neuropathology and Experimental Neurology, 2009
Neural stem cells persist after embryonic development in the subventricular zone (SVZ) niche and ... more Neural stem cells persist after embryonic development in the subventricular zone (SVZ) niche and produce new neural cells during postnatal life; ependymal cells are a key component associated with this neurogenic niche. In the animal model of human hydrocephalus, the hyh mouse, the ependyma of the lateral ventricles is progressively lost during late embryonic and early postnatal life and disappears from most of the ventricular surface throughout its life span. To determine the potential consequences of this loss on the SVZ, we characterized the abnormalities in this neurogenic niche in hyh mice. There was overall disorganization and a marked reduction of proliferative cells in the SVZ of both newborn and adult hyh hydrocephalic mice in vivo; neuroblasts were displaced to the ventricular surface, and their migration through the rostral migratory stream was reduced. The numbers of resident neural progenitor cells in hyh mice were also markedly reduced, but they were capable of proliferating, forming neurospheres, and differentiating into neurons and glia in vitro in a manner indistinguishable from that of wild-type progenitor cells. These findings suggest that the reduction of proliferative activity observed in vivo is not caused by a cell autonomous defect of SVZ progenitors but is a consequence of a reduced number of these cells. Furthermore, the overall tissue disorganization of the SVZ and displacement of neuroblasts imply alterations in the neurogenic niche of postnatal hyh mice.
BackgroundHyh mutant mice suffer a congenital hydrocephalus triggered by ependyma denudation [1].... more BackgroundHyh mutant mice suffer a congenital hydrocephalus triggered by ependyma denudation [1]. The ventricular surface in non hydrocephalic newborn mice is lined by the immature ependyma, which is characterized for being vimentin (-) and S100β (-), at variance in the adult animals the mature ependyma expresses vimentin and S100β [2]. On the other hand, in the hydrocephalic mice the ependyma begins to denudate on the 12th day of gestation, and at PN8 only some areas of lateral ventricle are still endowed with ependyma. In parallel, astroglia starts to cover the denuded surface forming a new cell layer, the glial scar, which lines the damaged ventricular surface. We have studied the permeability to horseradish peroxidase (HRP) of these four regions at the ventricular wills: mature ependyma, and denuded areas with or without glial scar.Materials and methodsControl and hydrocephalic hyh mice (Jackson Lab., USA) at 3rd and 30th day of post-natal life were injected into a lateral ventricl ...
BackgroundThe hyh (hydrocephalus with hop gait) mutant mice develop inherited hydrocephalus. A ke... more BackgroundThe hyh (hydrocephalus with hop gait) mutant mice develop inherited hydrocephalus. A key feature in this mutant is that there is a foetal-onset ependymal denudation which precedes cerebral aqueduct obliteration and hydrocephalus [1]. Recently, a point mutation in alpha-SNAP protein has been identified as responsible of the hyh phenotype [2]. However, preliminary findings from our laboratory have suggested clinical and pathological heterogeneity in the expression of hydrocephalus, indicating that other (nongenetic?) factors may influence the degree of severity of this pathology. This is in accordance with findings in other hydrocephalic mutant strains [3, 4]. The present investigation was designed to (a) study the clinical evolution of hydrocephalic mice in order to evaluate wether or not clinical heterogeneity does actually occur, (b) identify nongenetic factors (maternal age, multiparity) that may affect such an evolution, and (c) identify neuropathologic events underlying c ...
A heterogeneous population of ependymal cells lines the brain ventricles. The evidence about the ... more A heterogeneous population of ependymal cells lines the brain ventricles. The evidence about the origin and birth dates of these cell populations is scarce. Furthermore, the possibility that mature ependymal cells are born (ependymogenesis) or self-renewed (ependymal proliferation) postnatally is controversial. The present study was designed to investigate both phenomena in wild-type (wt) and hydrocephalic α-SNAP mutant (hyh) mice at different postnatal stages. In wt mice, proliferating cells in the ventricular zone (VZ) were only found in two distinct regions: the dorsal walls of the third ventricle and Sylvian aqueduct (SA). Most proliferating cells were monociliated and nestin+, likely corresponding to radial glial cells. Postnatal cumulative BrdU-labeling showed that most daughter cells remained in the VZ of both regions and they lost nestin-immunoreactivity. Furthermore, some labeled cells became multiciliated and GLUT-1+, indicating they were ependymal cells born postnatally. Postnatal pulse BrdU-labeling and Ki-67 immunostaining further demonstrated the presence of cycling multiciliated ependymal cells. In hydrocephalic mutants, the dorsal walls of the third ventricle and SA expanded enormously and showed neither ependymal disruption nor ventriculostomies. This phenomenon was sustained by an increased ependymogenesis. Consequently, in addition to the physical and geometrical mechanisms traditionally explaining ventricular enlargement in fetal-onset hydrocephalus, we propose that postnatal ependymogenesis could also play a role. Furthermore, as generation of new ependymal cells during postnatal stages was observed in distinct regions of the ventricular walls, such as the roof of the third ventricle, it may be a key mechanism involved in the development of human type 1 interhemispheric cysts.
In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) s... more In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) stenosis and heterotopias] is poorly understood. In animal models, loss of ventricular lining (ependymal denudation) causes SA stenosis and hydrocephalus. We aimed to investigate whether ependymal denudation also takes place in human foetal SBA. Considering that ependymal denudation would be related to alterations in junction proteins, sections through SA of five SBA and six control foetuses (gestational ages ranged between 37 and 40 weeks) were immunostained for markers of ependyma (caveolin 1, βIV-tubulin, S100), junction proteins (N-cadherin, connexin-43, neural cell adhesion molecule (NCAM), blood vessels (Glut-1) and astrocytes [glial fibrillary acidic protein (GFAP)]. In control foetuses, ependymal denudation was absent. In SBA foetuses different stages of ependymal denudation were observed: (i) intact ependyma/neuroepithelium; (ii) imminent ependymal denudation (with abnormal subcellular location of junction proteins); (iii) ependymal denudation (with protrusion of neuropile into SA, formation of rosettes and macrophage invasion); (iv) astroglial reaction. It is suggested that abnormalities in the formation of gap and adherent junctions result in defective ependymal coupling, desynchronized ciliary beating and ependymal denudation, leading to hydrocephalus. The presence of various stages of ependymal denudation within the same full-term SBA foetuses suggests continuation of the process after birth.
Journal of Neuropathology and Experimental Neurology, 2009
Neural stem cells persist after embryonic development in the subventricular zone (SVZ) niche and ... more Neural stem cells persist after embryonic development in the subventricular zone (SVZ) niche and produce new neural cells during postnatal life; ependymal cells are a key component associated with this neurogenic niche. In the animal model of human hydrocephalus, the hyh mouse, the ependyma of the lateral ventricles is progressively lost during late embryonic and early postnatal life and disappears from most of the ventricular surface throughout its life span. To determine the potential consequences of this loss on the SVZ, we characterized the abnormalities in this neurogenic niche in hyh mice. There was overall disorganization and a marked reduction of proliferative cells in the SVZ of both newborn and adult hyh hydrocephalic mice in vivo; neuroblasts were displaced to the ventricular surface, and their migration through the rostral migratory stream was reduced. The numbers of resident neural progenitor cells in hyh mice were also markedly reduced, but they were capable of proliferating, forming neurospheres, and differentiating into neurons and glia in vitro in a manner indistinguishable from that of wild-type progenitor cells. These findings suggest that the reduction of proliferative activity observed in vivo is not caused by a cell autonomous defect of SVZ progenitors but is a consequence of a reduced number of these cells. Furthermore, the overall tissue disorganization of the SVZ and displacement of neuroblasts imply alterations in the neurogenic niche of postnatal hyh mice.
BackgroundHyh mutant mice suffer a congenital hydrocephalus triggered by ependyma denudation [1].... more BackgroundHyh mutant mice suffer a congenital hydrocephalus triggered by ependyma denudation [1]. The ventricular surface in non hydrocephalic newborn mice is lined by the immature ependyma, which is characterized for being vimentin (-) and S100β (-), at variance in the adult animals the mature ependyma expresses vimentin and S100β [2]. On the other hand, in the hydrocephalic mice the ependyma begins to denudate on the 12th day of gestation, and at PN8 only some areas of lateral ventricle are still endowed with ependyma. In parallel, astroglia starts to cover the denuded surface forming a new cell layer, the glial scar, which lines the damaged ventricular surface. We have studied the permeability to horseradish peroxidase (HRP) of these four regions at the ventricular wills: mature ependyma, and denuded areas with or without glial scar.Materials and methodsControl and hydrocephalic hyh mice (Jackson Lab., USA) at 3rd and 30th day of post-natal life were injected into a lateral ventricl ...
BackgroundThe hyh (hydrocephalus with hop gait) mutant mice develop inherited hydrocephalus. A ke... more BackgroundThe hyh (hydrocephalus with hop gait) mutant mice develop inherited hydrocephalus. A key feature in this mutant is that there is a foetal-onset ependymal denudation which precedes cerebral aqueduct obliteration and hydrocephalus [1]. Recently, a point mutation in alpha-SNAP protein has been identified as responsible of the hyh phenotype [2]. However, preliminary findings from our laboratory have suggested clinical and pathological heterogeneity in the expression of hydrocephalus, indicating that other (nongenetic?) factors may influence the degree of severity of this pathology. This is in accordance with findings in other hydrocephalic mutant strains [3, 4]. The present investigation was designed to (a) study the clinical evolution of hydrocephalic mice in order to evaluate wether or not clinical heterogeneity does actually occur, (b) identify nongenetic factors (maternal age, multiparity) that may affect such an evolution, and (c) identify neuropathologic events underlying c ...
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