Jackson, E.L. et al. PDGFR-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron 51, 187-199

Department of Neurological Surgery and Program in Developmental and Stem Cell Biology, University of California, San Francisco, San Francisco, California 94143, USA.
Neuron (Impact Factor: 15.05). 08/2006; 51(2):187-99. DOI: 10.1016/j.neuron.2006.06.012
Source: PubMed


Neurons and oligodendrocytes are produced in the adult brain subventricular zone (SVZ) from neural stem cells (B cells), which express GFAP and have morphological properties of astrocytes. We report here on the identification B cells expressing the PDGFRalpha in the adult SVZ. Specifically labeled PDGFRalpha expressing B cells in vivo generate neurons and oligodendrocytes. Conditional ablation of PDGFRalpha in a subpopulation of postnatal stem cells showed that this receptor is required for oligodendrogenesis, but not neurogenesis. Infusion of PDGF alone was sufficient to arrest neuroblast production and induce SVZ B cell proliferation contributing to the generation of large hyperplasias with some features of gliomas. The work demonstrates that PDGFRalpha signaling occurs early in the adult stem cell lineage and may help regulate the balance between oligodendrocyte and neuron production. Excessive PDGF activation in the SVZ in stem cells is sufficient to induce hallmarks associated with early stages of tumor formation.

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Available from: Jose Manuel Garcia-Verdugo
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    • "Adult neurogenesis is a multistep process in which neural stem cell (NSC) lineages progress through a series of well characterized cell stages to generate functional interneurons in the olfactory bulb and hippocampal dentate gyrus (Ming and Song, 2011; Lim and Alvarez-Buylla, 2014). In the subventricular zone (SVZ), quiescent radial glial-like (RGL) progenitor cells are the multi-potent NSC population (Doetsch et al., 1999) and are capable of undergoing symmetrical cell division to maintain the stem cell pool and asymmetric cell division to generate rapidly dividing transit amplifying cells (also referred to as intermediate progenitors), as well as astrocytes and oligodendrocytes (Doetsch et al., 1997; Jackson et al., 2006; Bonaguidi et al., 2011). Transit amplifying cells differentiate into neuroblasts that migrate to the olfactory bulb through the rostral migratory stream (RMS) to settle as interneurons in the periglomerular and granule cell layers (Lois et al., 1996; Alvarez-Buylla and Garcia-Verdugo, 2002; Ming and Song, 2011). "
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    ABSTRACT: The role of epigenetic regulators in the control of adult neurogenesis is largely undefined. We show that the histone demethylase enzyme Kdm5b (Jarid1b) negatively regulates neurogenesis from adult subventricular zone (SVZ) neural stem cells (NSCs) in culture. shRNA-mediated depletion of Kdm5b in proliferating adult NSCs decreased proliferation rates and reduced neurosphere formation in culture. When transferred to differentiation culture conditions, Kdm5b-depleted adult NSCs migrated from neurospheres with increased velocity. Whole genome expression screening revealed widespread transcriptional changes with Kdm5b depletion, notably the up-regulation of reelin (Reln), the inhibition of steroid biosynthetic pathway component genes and the activation of genes with intracellular transport functions in cultured adult NSCs. Kdm5b depletion increased extracellular reelin concentration in the culture media and increased phosphorylation of the downstream reelin signaling target Disabled-1 (Dab1). Sequestration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed the increase in migratory velocity of Kdm5b-depleted adult NSCs. Chromatin immunoprecipitation revealed Kdm5b is present at the proximal promoter of Reln and H3K4me3 methylation was increased at this loci with Kdm5b depletion in differentiating aNSCs. Combined the data suggest Kdm5b negatively regulates neurogenesis and represses Reln in neural stem cells from the adult SVZ.
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    • "Mutations activating receptor tyrosine kinase-PI3K-mTOR signaling, including platelet-derived growth factor (PDGF) receptors , are common in low-grade gliomas, and increased PDGF signaling induces glioma-like growths from the subventricular zone (SVZ) in mice (Jackson et al., 2006; Suzuki et al., 2015). We addressed whether Notch signaling cells contribute to growth factor-induced hyperplasias in the brain and infused PDGF into the lateral ventricle of adult Hes5::GFP Notch-reporter mice (Figures 1A–1E). "
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    ABSTRACT: In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jκ, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma subtypes, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP-Jκ and p53 induces primitive neuroectodermal-like tumors in mice. Hence, Notch signaling cooperates with p53 to restrict cell proliferation and tumor growth in mouse models of human brain tumors.
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    • "It is possible that a common cell of origin, such as the previously proposed neural stem cell (Galli et al., 2004), exists for all GBMs and that the classes presented here result from distinct differentiation paths. However, the presence of precursor cells with selfreplicating ability in the brain, such as cells expressing stem cell markers and PDGFRA or EGFR (Jackson et al., 2006), suggests that multiple stem cell-like populations exist. Although there is a clear need for conclusive evidence supporting this hypothesis, it is at least striking to find the same genes as markers of two of the four classes lending support for a difference in cell of origin. "
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    ABSTRACT: The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.
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