Neural Stem Cells In Subventricular Zone Research Articles

Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones

Neural precursors persist throughout life in the rodent forebrain subventricular zone (SVZ) and hippocampal dentate gyrus. The regulation of persistent neural stem cells is poorly understood, in part because of the lack of neural progenitor markers. The Sox B1 subfamily of HMG-box transcription factors (Sox1-3) is expressed by precursors in the embryonic nervous system, where these factors maintain neural progenitors in an undifferentiated state while suppressing neuronal differentiation. Sox2 expression persists in germinative zones of the adult rodent brain, but Sox3 expression in the postnatal brain remains largely unexplored. Here we examine Sox3 expression in the neonatal and adult mouse brain to gain insight into its potential involvement in regulating persistent neural stem cells and neurogenesis. We also investigate Sox3 expression during expansion and neural differentiation of postnatal mouse SVZ neural stem cell and human embryonic stem cell (hESC) cultures. We find that Sox3 is expressed transiently by proliferating and differentiating neural progenitors in the SVZ-olfactory bulb pathway and dentate gyrus. Sox3 immunoreactivity also persists in specific postmitotic neuronal populations. In vitro, high Sox3 protein expression levels in undifferentiated, SVZ-derived neurospheres decline markedly with differentiation. Sox3 immunoreactivity in hESCs appears upon differentiation to neural progenitors and then decreases as cells differentiate further into neurons. These findings suggest that Sox3 labels specific stages of hESC-derived and murine neonatal and adult neural progenitors and are consistent with a role for Sox3 in neural stem cell maintenance. Persistent Sox3 expression in some mature neuronal populations suggests additional undefined roles for Sox3 in neuronal function.

Neurogenesis in the adult rat brain after intermittent hypoxia

Intermittent hypoxia has been found to prevent brain injury and to have a protective role in the CNS. To address the possible causes of this phenomenon, we made investigative effort to find out whether intermittent hypoxia affects neurogenesis in the adult rat brain by examining the newly divided cells in the subventricular zone (SVZ) and dentate gyrus (DG). The adult rats were treated with 3000 and 5000 m high altitude 4 h per day for 2 weeks consecutively. 5-Bromo-2-deoxyuridine-5-monophosphate (BrdU) immunocytochemistry demonstrated that the BrdU-labeled cells in the SVZ and DG increased after 3000 and 5000 m intermittent hypoxia. The number of BrdU-labeled cells in the SVZ returned to normal level 4 weeks following intermittent hypoxia. However, the BrdU-labeled cells in the DG had a twofold increase 4 weeks subsequent to intermittent hypoxia. From these data, we conclude that intermittent hypoxia facilitates the proliferation of neural stem cells in situ, and that the newly divided cells in the SVZ and DG react differently to hypoxia. We are convinced by these findings that the proliferation of neural stem cells in SVZ and DG may contribute to adaptive changes following intermittent hypoxia.

Subventricular zone neural stem cells remodel the brain following traumatic injury in adult mice.

Neural stem cells have recently been shown to contribute to the cellular remodeling that occurs following traumatic brain injury (TBI). Potential sources for these stem cells from within the brain include the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus. Using intraventricular injections of the fluorescent vital dye DiO in mice, we demonstrate that the subventricular zone population of stem cells can be reliably labeled and followed over time. By following these injections with a contralateral controlled cortical injury we demonstrate that cells from the subventricular zone migrate to the most proximally injured cortical areas. Using doublelabeling immunohistochemistry with anti-nestin, anti-GFAP, and anti-NeuN antibodies we demonstrate that labeled cells from the subventricular zone contribute primarily to the astroglial scar following injury. We do not observe any contribution to deeper areas of injury including the hippocampus. These data demonstrate that the subventricular zone contributes to brain remodeling following TBI, though neural stem cell sources outside the subventricular zone appear to play reparative roles as well.

Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone.

The subventricular zone (SVZ) of the lateral ventricles, the largest remaining germinal zone of the adult mammalian brain, contains an extensive network of neuroblasts migrating rostrally to the olfactory bulb. Little is known about the endogenous proliferation signals for SVZ neural stem cells or guidance cues along the migration pathway. Here we show that the receptor tyrosine kinases EphB1-3 and EphA4 and their transmembrane ligands, ephrins-B2/3, are expressed by cells of the SVZ. Electron microscopy revealed ephrin-B ligands associated with SVZ astrocytes, which function as stem cells in this germinal zone. A three-day infusion of the ectodomain of either EphB2 or ephrin-B2 into the lateral ventricle disrupted migration of neuroblasts and increased cell proliferation. These results suggest that Eph/ephrin signaling is involved in the migration of neuroblasts in the adult SVZ and in either direct or indirect regulation of cell proliferation.