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. Author manuscript; available in PMC: 2012 Jul 1.
Published in final edited form as: J Neuropathol Exp Neurol. 2011 Jul;70(7):622–633. doi: 10.1097/NEN.0b013e31822200aa

Comparative Characterization of the Human and Mouse Third Ventricle Germinal Zones

Sonika Dahiya 1, Da Yong Lee 2, David H Gutmann 2
PMCID: PMC3127083  NIHMSID: NIHMS300334  PMID: 21666496

Abstract

Recent evidence indicates differences in neural stem cell (NSC) biology in different brain regions. For example, we demonstrated that neurofibromatosis-1 (NF1) tumor suppressor gene inactivation leads to increased NSC proliferation and gliogenesis in the optic chiasm and brainstem, but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) vs. the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mice and human brains. In children but not adult humans the tv-SVZ contains nestin-positive, glial fibrillary acidic protein (GFAP)-positive, brain fatty acid binding protein-positive and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells, but lacks GFAP-positive, nestin-positive radial glia. As in the lateral ventricle SVZ (lv-SVZ), proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models.

Keywords: Germinal zone, Third ventricle

INTRODUCTION

With the emergence of the cancer stem cell hypothesis (1-4), considerable attention has focused on the lateral ventricle subventricular zone (lv-SVZ) as a potential germinal zone relevant to the genesis of high-grade gliomas in adults (5-7). Studies pioneered by Alvarez-Buylla et al have shown that neuroglial progenitor cells lining the lv-SVZ are authentic stem cells with the capability of producing all 3 major brain cell lineages (8-11). The existence of this specialized germinal zone in adults has prompted studies of the consequence of introducing glioma-associated genetic mutations into stem-like cells within the lv-SVZ. The ability to generate high-grade gliomas supports the hypothesis that gliomas arise from this specialized stem cell niche in adults (12-15).

In contrast to their adult counterparts, gliomas in children arise less commonly in the cerebral hemispheres and more often develop in the optic nerve, brainstem, and cerebellum (16). This spatial pattern of gliomagenesis is illustrated by World Health Organization grade I gliomas (pilocytic astrocytoma), which arise in the cerebellum (33%), optic pathway (27%), brainstem (16%), and cerebrum (13%) (17). Moreover, pilocytic astrocytomas arising in the context of the neurofibromatosis-1 (NF1) cancer predisposition syndrome are located predominantly in the optic pathway (67%), and less commonly form in other brain regions (18). The predilection for pediatric gliomas to form in these regions raises the possibility that additional germinal zones may contribute to the genesis of gliomas in children.

Because pediatric gliomas often arise in the optic pathway and hypothalamus, we sought to characterize an understudied potential germinal zone (i.e. the third ventricle) in human and mouse specimens. The location of the third ventricle (proximate to the hypothalamus and optic pathway) raises the possibility that optic nerve/hypothalamic gliomas arise from this unique ventricular zone. Support for regional heterogeneity in neuroglial cell function derives from our recent studies demonstrating that astrocytes and neural stem cells from different regions of the brain harbor region-specific transcriptomal signatures (19) and exhibit differential cell-autonomous responses to the pediatric brain cancer-causing genetic mutation (Nf1 gene inactivation) (20).

In this report, we characterize the third ventricle subventricular zone (tv-SVZ) in young and adult mouse and human brains

MATERIALS AND METHODS

Human Brain Samples

Samples were obtained at autopsy from the brains of 10 normal children (7 days to 4 years of age; mean = 9.6 months) and 10 adults (47-87 years of age; mean = 64.3 years) (Table, Supplemental Digital Content 1, http://links.lww.com/NEN/A246). A midline section of the tv-SVZ was embedded in paraffin and 5-μm-thick consecutive sections were cut. The lv-SVZ was represented in 10 cases (5 from each group). Mouse and human specimens are denoted by “m” and “h”, respectively. The SVZ was the region that encompassed both the ependymal lining and an adjacent 1-3 mm subependymal zone (SEZ) along the ventricular wall. Autopsy specimens were obtained in accordance with an approved Human Studies protocol at the Washington University School of Medicine.

Animals

Brain tissues were obtained from wild-type C57BL/6 mice at postnatal day 2-3 (young) and at 4-6 months of age (adult) following intracardiac perfusion with PBS and 4% paraformaldehyde solution. After fixation the specimens were paraffin-embedded. The mice were used in accordance with an approved Animal Studies protocol at the Washington University School of Medicine.

Routine Histology and Immunohistochemistry

Hematoxylin and eosin and immunohistochemical staining using lineage-specific antibodies were performed following antigen retrieval (Table, Supplemental Digital Content 2, http://links.lww.com/NEN/A247). Immunohistochemistry was performed simultaneously on all sections with appropriate positive and negative controls. Double labeling was performed using separate antigen retrieval buffers when required. Three different peroxidase substrates were used: Vector- 3′3′ diaminobenzidine (SK-4100), Vector-NovaRED (SK-4800) and Vector-SG (SK-4700), all from Vector Laboratories, Burlingame, CA. The Ki-67 labeling index was defined as the number of Ki-67-positive cells divided by the total number of cells (including both Ki-67-positive and Ki-67-negative cells) counted. Only cells in the SVZ (both positive and negative for Ki-67) were counted. Appropriate Alexa Fluor-tagged secondary antibodies were used for fluorescence detection and the cells were counterstained with DAPI.

For ultrastructural analysis, a portion of the SVZ was fixed in 2% glutaraldehyde, post-fixed in phosphate-buffered 2% OsO4 for 2 hours, dehydrated in graded concentrations of ethanol and embedded in Embed-812 (Electron Microscopy Sciences, Hatfield, Pennsylvania) with propylene oxide as an intermediary solvent. One-μm-thick plastic sections were stained with toluidine blue and examined under light microscopy to define the orientation of the ependymal layer and SVZ. Ultrathin sections were subsequently stained with uranyl acetate and lead citrate and examined with a JEOL 1200 electron microscope equipped with an ABT digital camera.

Statistical Analysis

Statistical significance (p < 0.05) was determined using the Student t-test and GraphPad Prism 4.0 software (GraphPad, Inc., La Jolla, CA).

RESULTS

Human tv-SVZ

We first compared the ventricular lining (ependyma) and SEZ extending 1 to 3 mm beneath the ependyma in human specimens. In children less than 5 years of age (n = 10), the ependyma is a single layered tall columnar epithelium with prominent cilia and a conspicuous terminal bar (Fig. 1A). In adults (older than 45 years; n = 10), the ependyma appears as a single-layer of cuboidal cells with a marked reduction in cilia (Fig. 1B). The presence of cilia was confirmed using acetylated tubulin immunostaining (Fig. 1C, D) and electron microscopy (Fig. 1E, F; arrow). In addition, the subependymal zone is paucicellular in adults compared to children. On ultrastructural examination, the tv-SVZ in adults is also paucicellular and the ependymal cells contain lipofuscin.

Figure 1.

Figure 1

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Age-dependent changes in the human third ventricle subventricular zone (tv-SVZ). (A, B) Section of the third ventricle from a child (A) reveals a single layered tall columnar epithelium with prominent cilia at the ventricular surface (inset). In an adult the ependymal layer is flattened and contains a single layer of cuboidal cells and there is marked reduction of lining cilia (B). (C, D) Acetylated tubulin immunostaining reveals abundant cilia in a pediatric (C) and few in an adult (D) tv-SVZ. Scale bars = 20 μm. (E, F) Electron microscopy demonstrates a relative abundance of cilia in a pediatric tv-SVZ (E; arrow), and the presence of lipopigment in lining ependymal cells in an adult tv-SVZ (F; arrow). A, B: Hematoxylin and eosin.

Immunohistochemistry using with antibodies that delineate neurons (Tuj1, polysialated neural cell adhesion molecule [PSA-NCAM], and NeuN), astrocytes (GFAP), and progenitor cells (nestin, vimentin, Sox2 and brain fatty acid binding protein [BLBP]) was performed to characterize the cellular composition of the human tv-SVZ. Several differences were noted between the pediatric and adult tv-SVZ specimens. First, GFAP-immunoreactive cells in the third ventricle SEZ of children had a radial appearance with prominent radial glial processes (Fig. 2A); however, in adults, GFAP immunostaining revealed a cobweb appearance with haphazard arrangements of glial processes (Fig. 2B). Second, numerous long perpendicularly oriented, nestin-immunoreactive processes arranged in parallel were found to extend from the ependymal layer into the SEZ in young children (Fig. 2C), whereas in adults there was only coarse punctate nestin staining in the subependymal region with more labeling at the base of the ependymal lining (Fig. 2D). In children, numerous cells with radial processes in the ependymal lining were immunopositive for both nestin and GFAP (Fig. 2E), and for BLBP (Fig. 2F); these data support their designation as radial glia. A small number of cells in the ependymal layer and SEZ also expressed the Sox2 progenitor marker (Fig. 2G). No differences in vimentin immunoreactivity were noted between the 2 age groups (data not shown). Third, the Tuj1- and PSA-NCAM-immunoreactive cell processes abut the base of the ependymal layer in young children (Fig. 3A, C). In contrast, there are few neurons beneath the ependymal layer in adults, resulting in a hypocellular zone (Fig. 3B, D). NeuN immunohistochemistry demonstrated staining of neurons in the regions much deeper to the SEZ, but was negative in the third ventricle SEZ of either age group (data not shown).

Figure 2.

Figure 2

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Radial glia in the third ventricle subventricular zone (tv-SVZ) of children. (A-D) Immunostaining for glial fibrillary acidic protein (GFAP) (A, B) and nestin (C, D) demonstrate moderate staining in the ependymal lining of tv-SVZ in a child (A, C) and an adult (B, D). Radial processes (inset, arrows) were only observed in the tv-SVZ of the child; there is a cobweb-like pattern of expression in the adult third ventricle subependymal zone (SEZ) (inset). Arrowheads in C and D indicate blood vessels as internal positive immunostaining controls. (E) Radial glia in a pediatric tv-SVZ co-label (yellow) for GFAP (green) and nestin (red). Inset shows radial processes double positive for GFAP and nestin. (F) The radial glia also express brain fatty acid binding protein (BLBP: red, DAPI: blue). BLBP expression is also seen in isolated cells within the SEZ. (G) A small number of cells within the lining ependyma and tv-SEZ are Sox2-immunoreactive (arrows). Scale bars = 20 μm.

Figure 3.

Figure 3

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Age-dependent changes in neuronal architecture in the human third ventricle subventricular zone (tv-SVZ). (A-D) Immunostaining for (A, B) polysialated neural cell adhesion molecules (PSA-NCAM) (A, B) and Tuj-1 (C, D) shows intense staining of the processes abutting the third ventricle SEZ in a child (A, C), that is absent in the adult SEZ (B, D). The hypocellular region in the adult tv-SVZ is denoted by bars. Scale bar = 20 μm.

Ki67 immunolabeling was used to determine the proliferative indices within the tv-SVZ (MIB-1). In general, proliferating cells were predominantly located in the immediate SEZ, with a very few Ki67-positive ependymal cells. There was a 14-fold reduction in the Ki-67 labeling index in adults vs. children (n = 10 specimens, p = 0.04) (Fig. 4). To determine which cells in the SEZ were proliferating, Ki67 double labeling experiments were performed. The vast majority of the Ki67-positive cells did not co-label with GFAP (Fig. 5A, B), PSA-NCAM (data not shown), nestin (Fig. 5C), or Olig2 (data not shown). Only 10% of the Ki67-positive cells were GFAP-immunoreactive (glial progenitors or astrocytes), 5% to 7% were nestin-positive (glial progenitor or stem cells), 1% were Olig2-positive, and none were PSA-NCAM-immunoreactive.

Figure 4.

Figure 4

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Proliferation in the human third ventricle subventricular zone (tv-SVZ) decreases with age. (A) Diagram of the region containing the human third ventricle (red box). (B, C) Ki67 immunolabeling of the tv-SVZ in representative specimens from a child (B) and an adult (C). (D) Mean and SD of Ki67 labeling indices (p < 0.005). Scale bar: B, C = 20 μm.

Figure 5.

Figure 5

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Proliferating cells in the human third ventricle subventricular zone (tv-SVZ) are glial fibrillary acidic protein (GFAP)- and nestin-immunoreactive. (A) A small population of GFAP-positive cells in the third ventricle subependymal zone (SEZ) co-labels with Ki67. Inset demonstrates a representative Ki67-positive, GFAP-positive cell. (B) Similar results are shown with GFAP/Ki67 immunofluorescence double labeling. The arrow denotes a representative GFAP-positive, Ki67-positive cell. (C) A small number of nestin-positive cells in the human third ventricle SEZ co-labels with Ki67. Inset demonstrates a representative nestin-positive, Ki67-positive cell. Scale bar = 20 μm.

Mouse tv-SVZ

Several age-dependent features were noted in the mice. The third ventricle of young mice lacked cells with GFAP expression, whereas there was diffuse GFAP immunoreactivity in the ependymal lining in adult mice (Fig. 6C, D). Small numbers of GFAP-positive cells were also found in the third ventricle SEZ in the adult mice. There was little nestin expression in the third ventricle of young mice, while widespread nestin immunoreactivity was found in the ependymal lining of adult mice (Fig. 6E, F). This absence of GFAP-positive, nestin-positive radial glia in the mouse TVZ sharply contrasts with the human specimens, both in the tv-SVZ (Fig. 2) and the lv-SVZ of children (Figure, Supplemental Digital Content 3, http://links.lww.com/NEN/A248). Third, as in human pediatric tv-SVZ specimens, sox2 immunostaining identified progenitor cells in the tv-SVZ of young mice (Figure, Supplemental Digital Content 4, http://links.lww.com/NEN/A249). There was also an age-dependent reduction in cilia, as evidenced by acetylated tubulin immunohistochemistry (Fig. 6G, H), but there were no differences in the pattern of neuronal (PSA-NCAM, Tuj1) staining between young and adult mice (Fig. 7). As in the human specimens (Fig. 4), Ki67 labeling index in the tv-SVZ was much lower (45-fold) in adult vs. early postnatal mice (n = 5 mice/group, p = 0.007) (Fig. 8). This age-dependent reduction in germinal zone proliferation within the human tv-SVZ was also observed in human (Fig. 9A) and mouse (Fig. 9C) lv-SVZ.

Figure 6.

Figure 6

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Age-dependent changes in the cellular composition of the mouse third ventricle subventricular zone (tv-SVZ). (A, B) Representative hematoxylin and eosin-stained sections of the third ventricle in young and adult mice. (C, D) Glial fibrillary acidic protein (GFAP)-positive cells are barely detected in the third ventricle in a young mouse (C) whereas an adult mouse exhibits focal GFAP immunoreactivity with diffuse expression in ependymal cells (D). (E, F) Rare nestin-positive cells in a young mouse (E); an adult moue ependymal layer contains numerous nestin-immunopositive cells (F). Arrowheads indicate blood vessels, which serve as internal positive controls. (G, H) Acetylated tubulin immunostaining illustrates age-dependent reduction in the number of cilia. The cilia appear relatively shorter than those in the human tv-SVZ.

Figure 7.

Figure 7

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Age-dependent similarities in the cellular composition of the mouse third ventricle subventricular zone (tv-SVZ). (A-D) Similar patterns of polysialated neural cell adhesion molecule (PSA-NCAM) (A, B) and Tuj-1 in the tv-SEZ (C, D) are observed in young mice (A, C) and adult mice (B, D). No hypocellular zone is detected in the adult mouse tv-SVZ. Scale bar: 20 μm.

Figure 8.

Figure 8

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Proliferation in the mouse third ventricle subventricular zone (tv-SVZ) decreases with age. (A) Diagram of the region containing the mouse third ventricle (red box). (B, C) Ki67 immunolabeling of the tv-SVZ in a young mouse (B) and an adult mouse (C). Scale bar: 20 μm. (D) Mean and SD for the Ki67 labeling indices (p < 0.005).

Figure 9.

Figure 9

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Age-dependent decreases in ventricular zone proliferation in the mouse and human third ventricle subventricular zone (tv-SVZ) and lateral ventricle SVZ (lv-SVZ). (A-D) The Ki67 labeling index is reduced in the human lv-SVZ as a function of age (p = 0.01) (A). The Ki67 labeling index is reduced in the murine lv-SVZ as a function of age (p = 0.0004) (C). Diagrams of the regions containing the human (B) and mouse (D) lv-SVZ (red boxes).

DISCUSSION

We used immunohistochemistry and electron microscopy to demonstrate the existence of an additional germinal zone within the third ventricle in humans. The designation of the tv-SVZ as a stem cell niche comparable to the better-studied lv-SVZ is supported by several observations. First, we identified cells with long radial processes that express both GFAP and nestin. While nestin-immunoreactive cells have been previously reported in the rat tv-SVZ, it is not known whether these nestin-positive cells co-labeled with GFAP (21), as seen in our study. GFAP-positive/nestin-positive radial glia-like cells most likely represent type B cells, as originally proposed for the lv-SVZ (9-11). Second, there is robust expression of BLBP (brain fatty acid binding protein; FABP7), a marker of both radial glia and neural stem cells. In this regard, radial glia in the lv-SVZ have been shown to give rise to adult neural stem cells (22). Additionally, we have previously used a BLBP-Cre transgenic mouse strain to demonstrate that BLBP-positive cells can self renew in vitro and give rise to oligodendrocytes, astrocytes, and neurons (multi-lineage differentiation) in vitro and in vivo, consistent with their role as neural stem cells (23). Third, the pediatric tv-SVZ also contains Olig2-positive cells, another marker of progenitor cells in the brain (24). In this regard, Olig2 is universally expressed in gliomas (25), and its targeted inactivation abrogates gliomagenesis in genetically engineered mice (26). Fourth, we identified sox2-positive cells in the tv-SVZ of children. Sox2 is a transcription factor critical for the maintenance of neural progenitor identity (27), such that alterations in sox2 expression in genetically engineered mice leads to defects in astrocyte and neuronal differentiation (28, 29). Fifth, we found that the cells lining the tv-SVZ in children contained cilia. Previous studies in adult rat (30) and primates (31) identified cilia along the lateral walls of the tv-SVZ, but not in the ventral parts. In contrast, we did not identify significant numbers of cilia in the adult human tv-SVZ, but could identify ciliated ependymal lining cells in the adult mouse tv-SVZ. The importance of cilia to neural stem cell function is highlighted by several studies demonstrating that primary cilia are required for the formation of adult neural stem cells (32), regulate hippocampal neurogenesis (33), and characterize B cells within the adult lv-SVZ (34).

In addition, we found an age-dependent development of a hypocellular region within the third ventricle SEZ. While the functional significance of this hypocellular region has not been fully elucidated, previous studies have demonstrated the existence of a similar paucicellular zone in the human lv-SVZ of adults (7, 10). Interestingly, this hypocellular region is very thin or not present in the lv-SVZ of other species (7, 35), similar to our findings in mice.

Next, we examined proliferation in the tv-SVZ. We describe an age-dependent decrease in the proliferative index in adults relative to their pediatric counterparts. This finding parallels a similar reduction in lv-SVZ proliferation in adults vs. children, and likely reflects an overall decrease in germinal zone capacity over time (36). To identify the proliferating cells within the pediatric tv-SVZ, we performed a series of double-labeling experiments. While there were small numbers of proliferating nestin-positive, Olig2-positive and GFAP-positive cells in the tv-SVZ, transient-amplifying type C cells could not be definitively identified. Similar to analogous studies in the human lv-SVZ, it is highly likely that some of the Ki67-positive cells contained within the tv-SVZ are neural stem cells. Current studies are focused on defining the identity of the proliferating cells in the tv-SVZ and on determining whether distinct subpopulations of progenitor cells exist in this pediatric germinal zone.

To inform future studies employing genetically engineered small animal glioma models, we compared the lv-SVZ and tv-SVZ in mice. As in humans, we found that proliferation decreased significantly with age in the murine tv-SVZ. In contrast to their human counterparts, we were unable to identify GFAP-positive, nestin-positive cells with clear radial processes in young mice. However, we could identify cells expressing the CD133 and BLBP progenitor markers in the young murine tv-SVZ (data not shown) as well as ciliated ependymal lining cells. The fact that BLBP-positive and CD133-positive cells can generate new neurons and astrocytes in the embryonic mammalian brain (37-40), as well as in the adult avian brain (41, 42), supports the presence of an analogous third ventricle germinal zone in mice. This contention is further strengthened by numerous studies examining a group of midline structures along the rodent third and fourth ventricles, termed circumventricular organs (CVOs). These CVO structures contain progenitor cells that express nestin, GFAP, sox2 and vimentin (43). Moreover, neurospheres generated from CVO tissues can proliferate and undergo multi-lineage differentiation in vitro and in vivo (44). Along these lines, preliminary results in our laboratory have established the existence of BLBP-positive neural stem cells (NSCs) in the postnatal day 1-2 murine tv-SVZ with the ability to sustain long-term self-renewal and undergo multi-lineage differentiation into oligodendrocytes, astrocytes and neurons in vitro (D.Y. Lee and D.H. Gutmann, manuscript in preparation). These preliminary findings parallel previous reports describing the presence of NSCs from the adult tv-SVZ with the capacity to self-renew and undergo multi-lineage differentiation (45, 46).

The observation that NSCs exist in the tv-SVZ is intriguing in light of mouse modeling experiments in which specific high-grade glioma-associated genetic changes introduced into lv-SVZ progenitor cells result in glioma formation. In these studies, coordinate loss of NF1, PTEN, and p53 function in mouse lv-SVZ cells is sufficient to generate high-grade gliomas in subcortical and cortical regions (13). Similarly, the expression of mutant p53 proteins (15, 47), platelet-derived growth factor (14) or oncogenic KRas in lv-SVZ neural stem cells initiates gliomagenesis (12). Although the relevance of the tv-SVZ to gliomagenesis is currently not clear, studies in rodents have demonstrated that ciliated ependymal cells in the rat third ventricle can give rise to differentiated progeny (48, 49), and that GFAP-positive cells can derive from neuroepithelial cells lining the third ventricle to populate the optic tract along retinal ganglion cell projections (50) and hypothalamic parenchyma (51).

Current studies are focused on determining the consequence of introducing specific pediatric glioma-associated genetic changes (Nf1 loss; BRAF activation) on third ventricle NSC function. Coupled with spatially distinct microenvironmental conditions, heterogeneity in NSC niches may contribute significantly to the pattern of gliomagenesis and may uncover new targets for therapeutic drug design specific for glioma-maintaining stem cells in children and adults.

Supplementary Material

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ACKNOWLEDGMENTS

We acknowledge the excellent technical support from members of the Gutmann laboratory, and Lisa Snipes and Karen Green from the Division of Neuropathology. We are also thankful to Dr. Robert E. Schmidt, MD, PhD for his expert advice in interpretation of our ultrastructural examination.

This work was partially supported by a grant from the National Institutes of Health (1R01NS65547 to DHG).

Footnotes

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