BMP signaling through BMPRIA in astrocytes is essential for proper cerebral angiogenesis and formation of the blood-brain-barrier

Bone morphogenetic protein (BMP) signaling is involved in differentiation of neural precursor cells into astrocytes, but its contribution to angiogenesis is not well characterized. This study examines the role of BMP signaling through BMP type IA receptor (BMPRIA) in early neural development using a conditional knockout mouse model, in which Bmpr1a is selectively disrupted in telencephalic neural stem cells. The conditional mutant mice show a significant increase in the number of cerebral blood vessels and the level of vascular endothelial growth factor (VEGF) is significantly upregulated in the mutant astrocytes. The mutant mice also show leakage of immunoglobulin around cerebral microvessels in neonatal mice, suggesting a defect in formation of the blood–brain-barrier. In addition, astrocytic endfeet fail to encircle cortical blood vessels in the mutant mice. These results suggest that BMPRIA signaling in astrocytes regulates the expression of VEGF for proper cerebrovascular angiogenesis and has a role on in the formation of the blood–brain-barrier.     

Oligodendrocyte precursor cells generate pituicytes in vivo during neurohypophysis development

In the vertebrate brain, much remains to be understood concerning the origin of glial cell diversity and the potential lineage relationships between the various types of glia. Besides astrocytes and myelin-forming oligodendrocytes, other macroglial cell populations are found in discrete areas of the central nervous system (CNS). They share functional features with astrocytes and oligodendrocytes but also display specific characteristics. Such specialized cells, called pituicytes, are located in the neurohypophysis (NH). Our work focuses on the lineage of the pituicytes during rodent development. First, we show that cells identified with a combination of oligodendrocyte precursor cell (OPC) markers are present in the developing rat NH. In culture, neonatal NH progenitors also share major functional characteristics with OPCs, being both migratory and bipotential, i.e. able to give rise to type 2 astrocytes and oligodendrocytes. We then observe that, either in vitro or after transplantation into myelin-deficient Shiverer brain, pieces of NH generate myelinating oligodendrocytes, confirming the oligodendrogenic potentiality of NH cells. However, no mature oligodendrocyte can be found in the NH. This led us to hypothesize that the OPCs present in the developing NH might be generating other glial cells, especially the pituicytes. Consistent with this hypothesis, the OPCs appear during NH development before pituicytes differentiate. Finally, we establish a lineage relationship between olig1+ cells, most likely OPCs, and the pituicytes by fate-mapping experiments using genetically engineered mice. This constitutes the first demonstration that OPCs generate glial cells other than oligodendrocytes in vivo.     

Astrocyte‐specific activation of TNFR2 promotes oligodendrocyte maturation by secretion of leukemia inhibitory factor

Tumor necrosis factor (TNF) and its receptors TNFR1 and TNFR2 have pleiotropic effects in neurodegenerative disorders. For example, while TNFR1 mediates neurodegenerative effects in multiple sclerosis, TNFR2 is protective and contributes to remyelination. The exact mode of TNFR2 action, however, is poorly understood. Here, we show that TNFR2‐mediated activation of the PI3K‐PKB/Akt pathway in primary astrocytes increased the expression of neuroprotective genes, including that encoding the neurotrophic cytokine leukemia inhibitory factor (LIF). To investigate whether intercellular signaling between TNFR2‐stimulated astrocytes and oligodendrocytes plays a role in oligodendrocyte maturation, we established an astrocyte–oligodendrocyte coculture model, composed of primary astrocytes from huTNFR2‐transgenic (tgE1335) mice and oligodendrocyte progenitor cells (OPCs) from wild‐type mice, capable of differentiating into mature myelinating oligodendrocytes. In this model, selective stimulation of human TNFR2 on astrocytes, promoted differentiation of cocultured OPCs to myelin basic protein‐positive mature oligodendrocytes. Addition of LIF neutralizing antibodies inhibited oligodendrocyte differentiation, indicating a crucial role of TNFR2‐induced astrocyte derived LIF for oligodendrocyte maturation. GLIA 2014;62:272–283     

Stage‐specific requirement for cyclin D1 in glial progenitor cells of the cerebral cortex

Despite the vast abundance of glial progenitor cells in the mouse brain parenchyma, little is known about the molecular mechanisms driving their proliferation in the adult. Here we unravel a critical role of the G1 cell cycle regulator cyclin D1 in controlling cell division of glial cells in the cortical grey matter. We detect cyclin D1 expression in Olig2‐immunopositive (Olig2+) oligodendrocyte progenitor cells, as well as in Iba1+ microglia and S100β+ astrocytes in cortices of 3‐month‐old mice. Analysis of cyclin D1‐deficient mice reveals a cell and stage‐specific molecular control of cell cycle progression in the various glial lineages. While proliferation of fast dividing Olig2+ cells at early postnatal stages becomes gradually dependent on cyclin D1, this particular G1 regulator is strictly required for the slow divisions of Olig2+/NG2+ oligodendrocyte progenitors in the adult cerebral cortex. Further, we find that the population of mature oligodendrocytes is markedly reduced in the absence of cyclin D1, leading to a significant decrease in the number of myelinated axons in both the prefrontal cortex and the corpus callosum of 8‐month‐old mutant mice. In contrast, the pool of Iba1+ cells is diminished already at postnatal day 3 in the absence of cyclin D1, while the number of S100β+ astrocytes remains unchanged in the mutant. GLIA 2014;62:829–839     

NG2+ glial cells: a novel glial cell population in the adult brain

We describe a major glial cell population in the central nervous system (CNS) that can be identified by the expression of 2 cell surface molecules, the NG2 proteoglycan and the alpha receptor for platelet-derived growth factor (PDGF alphaR). In vitro and in the developing brain in vivo, NG2 and PDGF alphaR are expressed on oligodendrocyte progenitor cells but are down-regulated as the progenitor cells differentiate into mature oligodendrocytes. In the mature CNS, numerous NG2+/PDGF alphaR+ cells with extensive arborization of their cell processes are found ubiquitously long after oligodendrocytes are generated. NG2+ cells in the mature CNS do not express antigens specific to mature oligodendrocytes, astrocytes, microglia, or neurons, suggesting that they are a novel population of glial cells. Recently NG2+ cells in the adult CNS have been shown to undergo proliferation and morphological changes in response to a variety of stimuli, such as demyelination and inflammation, suggesting that they are dynamic cells capable of responding to changes in the environment. Furthermore, high levels of NG2+ and PDGF alphaR are expressed on oligodendroglioma cells, raising the possibility that the NG2+/PDGF alphaR+ cells in the mature CNS contribute to glial neoplasm.     

CD44-Positive Cells Are Candidates for Astrocyte Precursor Cells in Developing Mouse Cerebellum

Neural stem cells are generally considered to be committed to becoming precursor cells before terminally differentiating into either neurons or glial cells during neural development. Neuronal and oligodendrocyte precursor cells have been identified in several areas in the murine central nervous system. The presence of astrocyte precursor cells (APCs) is not so well understood. The present study provides several lines of evidence that CD44-positive cells are APCs in the early postnatal mouse cerebellum. In developing mouse cerebellum, CD44-positive cells, mostly located in the white matter, were positive for the markers of the astrocyte lineage, but negative for the markers of mature astrocytes. CD44-positive cells were purified from postnatal cerebellum by fluorescence-activated cell sorting and characterized in vitro. In the absence of any signaling molecule, many cells died by apoptosis. The surviving cells gradually expressed glial fibrillary acidic protein, a marker for mature astrocytes, indicating that differentiation into mature astrocytes is the default program for these cells. The cells produced no neurospheres nor neurons nor oligodendrocytes under any condition examined, indicating these cells are not neural stem cells. Leukemia inhibitory factor greatly promoted astrocytic differentiation of CD44-positive cells, whereas bone morphogenetic protein 4 (BMP4) did not. Fibroblast growth factor-2 was a potent mitogen for these cells, but was insufficient for survival. BMP4 inhibited activation of caspase-3 and greatly promoted survival, suggesting a novel role for BMP4 in the control of development of astrocytes in cerebellum. We isolated and characterized only CD44 strongly positive large cells and discarded small and/or CD44 weakly positive cells in this study. Further studies are necessary to characterize these cells to help determine whether CD44 is a selective and specific marker for APCs in the developing mouse cerebellum. In conclusion, we succeeded in preparing APC candidates from developing mouse cerebellum, characterized them in vitro, and found that BMPs are survival factors for these cells.     

Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4

Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We used a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic Day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation.     

Insulin-like growth factor type 1 receptor signaling in the cells of oligodendrocyte lineage is required for normal in vivo oligodendrocyte development and myelination

Insulin-like growth factor-I (IGF-I) has been shown to be a potent agent in promoting the growth and differentiation of oligodendrocyte precursors, and in stimulating myelination during development and following injury. To definitively determine whether IGF-I acts directly on the cells of oligodendrocyte lineage, we generated lines of mice in which the type 1 IGF receptor gene (igf1r) was conditionally ablated either in Olig1 or proteolipid protein expressing cells (termed IGF1R(pre-oligo-ko) and IGF1R(oligo-ko) mice, respectively). Compared with wild type mice, IGF1R(pre-oligo-ko) mice had a decreased volume (by 35-55%) and cell number (by 54-70%) in the corpus callosum (CC) and anterior commissure at 2 and 6 weeks of age, respectively. IGF1R(oligo-ko) mice by 25 weeks of age also showed reductions, albeit less marked, in CC volume and cell number. Unlike astrocytes, the percentage of NG2(+) oligodendrocyte precursors was decreased by approximately 13% in 2-week-old IGF1R(pre-oligo-ko) mice, while the percentage of CC1(+) mature oligodendrocytes was decreased by approximately 24% in 6-week-old IGF1R(pre-oligo-ko) mice and approximately 25% in 25-week-old IGF1R(oligo-ko) mice. The reduction in these cells is apparently a result of decreased proliferation and increased apoptosis. These results indicate that IGF-I directly affects oligodendrocytes and myelination in vivo via IGF1R, and that IGF1R signaling in the cells of oligodendrocyte lineage is required for normal oligodendrocyte development and myelination. These data also provide a fundamental basis for developing strategies with the potential to target IGF-IGF1R signaling pathways in oligodendrocyte lineage cells for the treatment of demyelinating disorders.     

Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes

The non-receptor protein tyrosine kinase Fyn, which is a member of the Src family of kinases, has been shown to be essential for normal myelination and has been suggested to play a role in oligodendrocyte development. However, oligodendrocyte development has not been studied directly in cells lacking Fyn. Additionally, because Fyn is expressed in neurons as well as oligodendrocytes, it is possible that normal myelination requires Fyn expression in neurons but not in oligodendrocytes. To address these issues, we analyzed the development of oligodendrocytes in neuron-free glial cell cultures from fyn(-/-) mice that express no Fyn protein. We observed that oligodendrocytes develop to the stage where they elaborate an extensive network of membranous processes and express the antigenic components of mature oligodendrocytes in the complete absence of Fyn. However, as compared with fyn(+/+) controls, fewer oligodendroglia developed in fyn(-/-) cell cultures, and a smaller proportion of them matured to the stage characterized by a high degree of morphological complexity. In addition, we found that insulin-like growth factor-I, a potent stimulator of oligodendrocyte development, failed to stimulate morphological maturation of fyn(-/-) oligodendroglia. The pyrazolopyrimidine PP2, believed to be a selective inhibitor of Fyn, did not prevent the development of morphologically complex oligodendrocytes. Unexpectedly, however, it was toxic to both fyn(+/+) and fyn(-/-) glial cells, indicating that this class of inhibitors can have significant effects that are independent of Fyn.     

Neurotransmitter-mediated calcium signalling in oligodendrocyte physiology and pathology

The function of oligodendrocytes is to myelinate CNS axons. Oligodendrocytes and the axons they myelinate are functional units, and neurotransmitters released by axons can influence all stages of oligodendrocyte development via calcium dependent mechanisms. Some of the clearest functional evidence is for adenosine, ATP, and glutamate, which are released by electrically active axons and regulate the migration and proliferation of oligodendrocyte progenitor cells and their differentiation into myelinating oligodendrocytes. Glutamate and ATP, released by both axons and astrocytes, continue to mediate Ca(2+) signaling in mature oligodendrocytes, acting via AMPA and NMDA glutamate receptors, and heterogeneous P2X and P2Y purinoceptors. Physiological signalling between axons, astrocytes, and oligodendrocytes is likely to play an important role in myelin maintenance throughout life. Significantly, ATP- and glutamate-mediated Ca(2+) signaling are also major components of oligodendrocyte and myelin damage in numerous pathologies, most notably ischemia, injury, periventricular leukomalacia, and multiple sclerosis. In addition, NG2-expressing glia (synantocytes) in the adult CNS are highly reactive cells that respond rapidly to any CNS insult by a characteristic gliosis, and are able to regenerate oligodendrocytes and possibly neurons. Glutamate and ATP released by neurons and astrocytes evoke Ca(2+) signaling in NG2-glia (synantocytes), and it is proposed these regulate their differentiation capacity and response to injury. In summary, clear roles have been demonstrated for neurotransmitter-mediated Ca(2+) signaling in oligodendrocyte development and pathology. A key issue for future studies is to determine the physiological roles of neurotransmitters in mature oligodendrocytes and NG2-glia (synantocytes).     

Down-regulation of GAP-43 During Oligodendrocyte Development and Lack of Expression by Astrocytes In Vivo: Implications for Macroglial Differentiation

The discovery of molecular markers which are selectively expressed during the development of specific classes of rat central nervous system macroglia has greatly advanced our understanding of how these cells are related. In particular, it has been shown in tissue culture that oligodendrocytes and some astrocytes (type-2) may be derived from a common progenitor cell (O-2A progenitor). However, the existence of type-2 astrocytes in vivo has yet to be unequivocally established. Recently, it has been reported that the neural-specific growth-associated protein-43 (GAP-43, otherwise known as B-50, F1, pp46 and neuromodulin) may be expressed by cells of the O-2A lineage in vitro. We set out to examine the cellular specificity of GAP-43 in O-2A progenitors and their descendants in vitro and in vivo. Using a polyclonal antiserum against a GAP-43 fusion protein we have shown the presence of immunoreactive GAP-43 in the membranes of bipotential O-2A glial progenitor cells and type-2 astrocytes by Western blotting and immunocytochemistry of cells in culture. In contrast to previous studies, double labelling with mature oligodendrocyte markers showed that GAP-43 is down-regulated during oligodendrocyte differentiation in vitro. Immunohistochemical staining of sections of developing rat brain demonstrated the same developmental regulation of GAP-43, suggesting that oligodendrocytes only express GAP-43 at immature stages. In addition, normal and reactive astrocytes in tissue sections were not labelled with GAP-43.     

Cuprizone [Bis(Cyclohexylidenehydrazide)] is Selectively Toxic for Mature Oligodendrocytes

Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental animal model commonly used to study de- and remyelination in the central nervous system. In this model, mice are fed with the copper chelator cuprizone which leads to oligodendrocyte death with subsequent demyelination. The underlying mechanisms of cuprizone-induced oligodendrocyte death are still unknown, and appropriate in vitro investigations to study these mechanisms are not available. Thus, we studied cuprizone effects on rat primary glial cell cultures and on the neuroblastoma cell line SH-SY5Y. Treatment of cells with different concentrations of cuprizone failed to show effects on the proliferation and survival of SH-SY5Y cells, microglia, astrocytes, and oligodendrocyte precursor cells (OPC). In contrast, differentiated mature oligodendrocytes (OL) were found to be significantly affected by cuprizone treatment. This was accompanied by a reduced mitochondrial potential in cuprizone-treated OL. These results demonstrate that the main toxic target for cuprizone is mature OL, whilst other glial cells including OPC are not or only marginally affected. This explains the selective demyelination induced by cuprizone in vivo.     

Concurrent isolation and characterization of oligodendrocytes, microglia and astrocytes from adult human spinal cord

A cellular preparation of highly enriched oligodendrocytes was obtained from adult human spinal cord by Percoll gradient centrifugation followed by either differential adhesion or fluorescence-activated cell sorting after immunostaining with an antibody against galactocerebroside (Ol). The adherent and O1-negative cell fractions were 96% microglia. The non-adherent and O1-positive fractions were 96% positive for the oligodendrocyte markers O4 and O1, 0–2% positive for glial fibrillary acidic protein, and were devoid of neuronal or microglial markers. If the oligodendrocyte fraction was co-cultured with purified dissociated rat dorsal root ganglion neurons, the oligodendrocytes adhered to the axons and their numbers increased over a 4 week period. However, myelin sheaths were not produced around axons in these cultures. In contrast, if the oligodendrocyte cell fraction was grown alone in culture for 3 weeks, the number of oligodendrocytes decreased and a layer of astrocytes developed underneath the oligodendrocytes. The oligodendrocytes could be eliminated from these cultures by subsequent passaging, thus producing cultures of pure astrocytes. The astrocytes accumulated both K⁺ and glutamate with kinetic properties similar to those reported for rodent astrocytes. We suggest that these astrocytes arose in part from an O4/O1-positive precursor which did not initially express glial fibrillary acidic protein. These results define a relatively simple method by which highly enriched populations of oligodendrocytes, astrocytes and microglia can be obtained from adult human spinal cord.     

Influence of LIF and BMP-2 on differentiation and development of glial cells in primary cultures of embryonic rat cerebral hemisphere

Cells prepared from the cerebral hemisphere of embryonic Day 18 rats were maintained for 2 days in serum-free modified Bottenstein-Sato (mBS) medium containing thyroid hormone (TH), with or without leukemia inhibitory factor (LIF) or bone morphogenetic protein (BMP)-2, and these influences on the differentiation and development of glial cells were investigated using the cells maintained in mBS medium containing TH as controls. The levels of glial fibrillary acidic protein (GFAP) expression and the number of GFAP-positive astrocytes increased markedly with the addition of LIF or BMP-2, and were enhanced further with the addition of both LIF and BMP-2. The number of O1-positive oligodendrocytes increased with the addition of LIF, whereas it decreased with the addition of BMP-2. The number did not change with the addition of both cytokines. Using antibody against platelet-derived growth factor (PDGF), we then excluded indirect effects of these cytokines through PDGF, which would increase by accelerated astrocyte development. When PDGF was neutralized, the number of oligodendrocytes increased under all conditions examined. As a result of the neutralization, the effect of BMP-2 on oligodendrocyte differentiation was eliminated, although LIF remained effective. These results suggest that the differentiation of oligodendrocytes was delayed partially by PDGF even in control cultures. It is also suggested that LIF and BMP-2, each of which accelerates the differentiation and development of astrocytes, would seem to have different effects on oligodendrocyte differentiation, i.e., LIF would directly affect oligodendrocyte differentiation, whereas BMP-2 would affect it mainly through PDGF.     

Pre-oligodendrocytes from adult human CNS.

CNS remyelination and functional recovery often occur after experimental demyelination in adult rodents. This has been attributed to the ability of mature oligodendrocytes and/or their precursor cells to divide and regenerate in response to signals in demyelinating lesions. To determine whether oligodendrocyte precursor cells exist in the adult human CNS, we have cultured white matter from patients undergoing partial temporal lobe resection for intractable epilepsy. These cultures contained a population of process-bearing cells that expressed antigens recognized by the O4 monoclonal antibody, but these cells did not express galactocerebroside (a marker for oligodendrocytes), glial fibrillary acidic protein (a marker for astrocytes), or vimentin. Selective elimination of O4-positive (O4+) cells by complement-mediated lysis resulted in inhibition of oligodendrocyte development in vitro. Since O4+ cells have an antigenic phenotype reminiscent of the rat adult oligodendrocyte-type 2 astrocyte progenitor and appear to develop into oligodendrocytes rather than type 2 astrocytes with time in culture, we call them "pre-oligodendrocytes." Neither pre-oligodendrocytes nor oligodendrocytes incorporated 3H-thymidine in response to rat astrocyte-conditioned medium, platelet-derived growth factor, insulin-like growth factor (IGF-1), or basic fibroblast growth factor (bFGF). However, IGF-1 increased the relative abundance of oligodendrocytes to pre-oligodendrocytes, while bFGF had the opposite effect. Cells with the antigenic phenotype of pre-oligodendrocytes were also identified in tissue prints of adult human white matter. We propose that, in human demyelinating diseases such as multiple sclerosis, pre-oligodendrocytes may divide and/or migrate in response to signals present in demyelinated lesions and thus facilitate remyelination.     

The microglial reaction in spinal cords of jimpy mice is related to apoptotic oligodendrocytes

Jimpy is a shortened life-span murine mutant whose genetic disorder results in a severe hypomyelination in the central nervous system associated with a variety of glial abnormalities, including oligodendrocyte death. In this study, we report that oligodendrocyte death in jimpy occurs through an apoptotic mechanism, as demonstrated by in situ labeling of nuclear DNA fragmentation. Compared to those of normal littermates, the spinal cords of jimpy mice showed a significantly higher number of apoptotic cells. Our observations also corroborate that specific glial cell death in jimpy is restricted to oligodendrocytes, as evidenced by double labeling for DNA fragmentation and MBP immunocytochemistry. Cells labeled for DNA fragmentation were always negative for astroglial or microglial markers. Apoptotic oligodendrocytes were not aggregated into clusters and were ubiquitously distributed throughout the jimpy spinal cord, although were more numerous in white matter than in gray matter. We found no physical association between astrocytes and dying cells in jimpy. Microglial cells, however, were found closely attached to and even surrounding apoptotic cells. The possible role of microglial cells in relation to apoptotsis is discussed.     

Polydendrocytes: NG2 cells with many roles in development and repair of the CNS.

NG2 cells, or polydendrocytes, are defined as glial cells that express the NG2 proteoglycan and represent a fourth major glial cell population in the mammalian central nervous system. They are morphologically, antigenically, and functionally distinct from mature astrocytes, oligodendrocytes, and microglia. Although they are most often equated with oligodendrocyte progenitor cells, they exhibit some properties that are not commonly associated with those of progenitor cells that generate myelinating cells. This review discusses recent observations and unanswered issues related to their lineage and their role in remyelination, neural signaling, and axonal growth.     

In vitro identification and functional characterization of glial precursor cells in human gliomas

Human gliomas including astrocytomas and oligodendrogliomas are defined as being composed of neoplastic astrocytes and oligodendrocytes respectively. Here, on the basis of in vitro functional assays, we show that gliomas contain a mixture of glial progenitor cells and their progeny. We have set up explant cultures from pilocytic astrocytomas, glioblastomas and oligodendrogliomas and studied antigens that characterize glial lineage, from the precursor cells (glial restricted precursors and oligodendrocyte-type2-astrocyte/oligodendrocyte precursor cells expressing the A2B5 ganglioside) to the differentiated cells (oligodendrocyte and type-1 and type-2 astrocytes). All tumoral explants contain A2B5+ cells and can generate migrating cells with distinctive functional properties according to glioma subtypes. In pilocytic astrocytomas, very few migrating cells are dividing and can differentiate in type-2 astrocytes or towards the oligodendrocyte lineage. In glioblastomas, most migrating cells are dividing, express A2B5 or glial fibrillary acid protein (GFAP) and can generate oligodendrocytes and type-1 and type-2 astrocytes in appropriate medium. Oligodendroglioma explants are made by actively dividing glial precursor cells expressing A2B5 or PSA-NCAM. Only few cells can migrate and differentiation towards oligodendrocyte lineage does not occur. Isolated A2B5+ cells from both glioblastomas and oligodendrogliomas showed similar genetic alterations as the whole tumour. Therefore, pilocytic astrocytomas contain slowly dividing oligodendrocyte-type2-astrocyte/oligodendrocyte precursor cells in keeping with their benign behaviour whereas both glioblastomas and oligodendrogliomas contain neoplastic glial restricted precursor cells. In oligodendrogliomas, these cells are trapped in undifferentiated and proliferating state. The precursor cells properties present in gliomas give new insight into their histogenesis and open up new avenues for research in the field of gliomagenesis.