Substantial migration of SVZ cells to the cortex results in the generation of new neurons in the excitotoxically damaged immature rat brain

Medical Histology, Department of Cell Biology, Physiology and Immunology, Neuroscience Institute, Autonomous University of Barcelona, Spain.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 07/2008; 38(2):170-82. DOI: 10.1016/j.mcn.2008.02.002
Source: PubMed


Mammalian SVZ progenitors continuously generate new neurons in the olfactory bulb. After injury, changes in SVZ cell number suggest injury-induced migration. Studies that trace the migration of SVZ precursors into neurodegenerating areas are lacking. Previously, we showed a decrease in BrdU+SVZ cells following excitotoxic damage to the immature rat cortex. Here, we demonstrate that NMDA-induced injury forces endogenous Cell Tracker Green (CTG) labeled VZ/SVZ precursors out of the SVZ into the neurodegenerating cortex. CTG+/Nestin+/Filamin A+ precursors are closely associated with vimentin+/GFAP+/GLAST+ filaments and express both chemokine receptor CXCR4 and Robo1. In the cortex, SVZ-derived progenitors show a progressive expression of developing, migrating and mature neurons and glial markers. CTG+/GFAP+ astrocytes greatly outnumber CTG+/MAP2+/NeuN+ neurons. SVZ-derived progenitors differentiate into both tbr1+ cortical glutamatergic neurons and calretinin+ interneurons. But, there is little integration of these neurons into the existing circuitry, as seen by Fluorogold retrograde tracing from the internal capsule.

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    • "Neural progenitors from the SVZ/RMS migrate to the lesion area It has been previously shown that in response to brain injury or degeneration, neural progenitors move out of the SVZ/RMS and migrate to the affected area (Arvidsson et al., 2002; Ramaswamy et al., 2005; Sundholm-Peters et al., 2005; Faiz et al., 2008). However, the migration pattern was not studied in detail. "
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    ABSTRACT: The subventricular zone (SVZ) is the principal neurogenic niche present in the adult non-human mammalian brain. Neurons generated in the SVZ migrate along the rostral migratory stream to reach the olfactory bulb. Brain injuries stimulate SVZ neurogenesis and direct migration of new progenitors to the sites of injury. To date, cortical injury-induced adult SVZ neurogenesis in mice remains ambiguous and migration of neural progenitors to the site of injury has not been studied in detail. Here we report that aspiration lesion in the motor cortex induces a transient, but significant increase in the proliferation as well as neurogenesis in the SVZ. New neural progenitors migrate ectopically to the injured area with the assistance of blood vessels and reactive astrocytes. The SVZ origin of these progenitors was further confirmed using lentiviral transduction. In addition, we show that astrocyte-assisted ectopic migration is regulated by CXCR4/SDF-1 signaling pathway. Finally, upon reaching the lesion area, these progenitors differentiate mainly into glial cells and, to a lesser extent, mature neurons. These data provide a detailed account of the changes occurring in the SVZ and the cortex following lesion, and indicate the potential of the endogenous neural progenitors in cortical repair.
    Full-text · Article · Jun 2013 · Stem Cell Research
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    • "2a–d and Fig. 3a–d were taken from, respectively. Scale bar is 1 mm J Mol Hist (2012) 43:215–221 217 (Pencea et al. 2001; Faiz et al. 2008), DCX (a microtubule-associated phosphoprotein expressed in migrating neuroblasts and differentiating neurons) (Nacher et al. 2001), and PSA-NCAM (polysialylated form of neural cell adhesion molecule) (Pencea et al. 2001). Those studies showed that migrating neuroblasts express general neuronal markers indicative of neural lineage selection, and here our results indicate that the major GAD lineages are also specify early. "
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    ABSTRACT: Olfactory bulb interneurons are continuously generated in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) into the olfactory bulb (OB) where the majority becomes local GABAergic interneurons. We previously showed that SVZ-derived progenitor cells expressed glutamic acid decarboxylase 65 kDa (GAD65) very early in the migratory pathway. However, only approximately half of OB GABAergic interneurons use GAD65, an equal number express the 67 kDa GAD enzyme. To investigate the differentiation of these GABAergic interneurons we examined their migration in a transgenic mouse expressing green fluorescent protein (GFP) under the control of the GAD67 promoter. In adult, GFP was expressed by a subpopulation of migratory cells in the SVZ and along the RMS. Using Doublecortin (DCX) as a marker of migrating neuroblasts and bromodeoxyuridine (BrdU) incorporation, we show that these GAD67-GFP neurons co-express DCX and incorporate BrdU indicating they are newly born migratory neuroblasts. This is similar to GAD65 transgene expression, and in contrast to dopaminergic interneuron transgene expression which occurs only after cells reach the olfactory bulb. Although the GAD65/67 transgenes are expressed early in migration, there is minimal protein production in the cells prior to reaching the OB. These results suggest that migrating SVZ-derived neuroblasts acquire GABAergic identity prior to reaching their final location in the olfactory bulb.
    Full-text · Article · Mar 2012 · Journal of molecular histology
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    • "The mechanisms controlling neuroblasts restriction to the RMS are also poorly understood; neuroblasts are restricted to the RMS and do not colonize surrounding brain areas other than in a few injury-related examples (Faiz et al., 2008). Migrating neuroblasts stop at the SVZ/ white matter border and turn back into the SVZ, suggesting a boundary between permissive/nonpermissive migratory zones (Suzuki and Goldman, 2003). "
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    ABSTRACT: The rostral migratory stream (RMS) is a well defined migratory pathway for precursors of olfactory bulb (OB) interneurons. Throughout the RMS an intense astroglial matrix surrounds the migratory cells. However, it is not clear to what extent the astroglial matrix participates in migration. Here, we have analyzed the migratory behavior of neuroblasts cultured on monolayers of astrocytes isolated from areas that are permissive (RMS and OB) and nonpermissive (cortex and adjacent cortical areas) to migration. Our results demonstrate robust neuroblast migration when RMS-explants are cultured on OB or RMS-astrocytes, in contrast to their behavior on astroglia derived from nonpermissive areas. These differences, mediated by astrocyte-derived nonsoluble factors, are related to the overexpression of extracellular matrix and cell adhesion molecules, as revealed by real-time qRT-PCR. Our results show that astroglia heterogeneity could play a significant role in migration within the RMS and in cell detachment in the OB.
    Full-text · Article · Aug 2009 · Glia
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