PDGFR-alpha (red) is expressed
in a subset of GFAP-expressing
cells (green) in the adult mouse
SVZ. Image courtesy of Erica
Jackson, University of California,
San Francisco, San Francisco.
In Greek mythology, the fates weaved the threads of human lives. In the brain, cell fate describes the ultimate identity that a cell will achieve through differentiation. The subventricular zone (SVZ) contains neural stem cells that can generate both neurons and glia even in adulthood. Glial fibrillary acidic protein (GFAP) is the only known marker for these pluripotent cells called B cells. Platelet-derived growth factor receptor-
(PDGFRa) is expressed in B cells and regulates the balance of neurons and glia in the adult brain, report Jackson et al. in a recent article in Neuron.
The authors found PDGFR expression in 83% of GFAP-positive B cells in the SVZ of the adult mouse, as shown by confocal microscopy. In contrast, PDGFR expression was not detected in the differentiated products of B cells. PDGFR did not colocalize with the C-cell marker epidermal growth factor receptor or the A-cell markers doublecortin and polysialylated neural cell adhesion molecule. The authors confirmed that PDGFR also localized to a subset of SVZ B cells in the adult human.
The authors used fate mapping to identify the cell types that arose from PDGFR-expressing SVZ B cells. PDGFR is a receptor for adeno-associated virus serotype 5 (AAV5), which incorporates into B cell DNA and is expressed in its cellular progeny. The authors treated mice with Ara-C to kill rapidly dividing C and A cells and induce slowly dividing B cells to replace them. They then injected these mice with AAV5-expressing green fluorescent protein (GFP) and identified GFP-positive neurons in the olfactory bulb and in the migratory stream terminating in the olfactory bulb. These data suggest that PDGFR-positive B cells are neuronal progenitors.
PDGFR-positive B cells also generated oligodendrocytes. The authors infected transgenic mice expressing the receptor for avian leukosis virus in GFAP-positive cells with AAV5-GFP and avian leukosis virus-expressing alkaline phosphatase. These mice had double-labeled oligodendrocytes in the corpus callosum. Therefore, PDGFR-positive B cells produced both neuron and oligodendrocyte precursors.
Surprisingly, 100% of mice infused for several days with PDGF-AA, a ligand specific to PDGFR, had tumor-like hyperplasias in the SVZ. The hyperplasias contained proliferating cells, at least some of which were derived from PDGFR-expressing B cells. Hyperplasias were not observed in mice withdrawn from PDGF-AA before death, suggesting that the tumor-like growths required growth factor stimulation. However, PDGF-AA withdrawn mice had fewer neurons in the olfactory bulb and more oligodendrocytes in the corpus callosum relative to uninjected controls. Mice lacking PDGFR in a small subset of adult neural stem cell precursors had fewer oligodendrocytes, but similar numbers of neurons, relative to controls. The authors therefore conclude that PDGFR regulates the balance of neurons and glia produced in the adult brain.
The hyperplasias induced by PDGF-AA infusion represent an early stage in tumor formation, according to the authors. Inhibition of PDGF signaling may therefore have therapeutic potential in treating brain tumors, which kill approximately 13,000 people a year.