Neuronal regeneration in a zebrafish model of adult brain injury.
ABSTRACT Neural stem cells in the subventricular zone (SVZ) of the adult mammalian forebrain are a potential source of neurons for neural tissue repair after brain insults such as ischemic stroke and traumatic brain injury (TBI). Recent studies show that neurogenesis in the ventricular zone (VZ) of the adult zebrafish telencephalon has features in common with neurogenesis in the adult mammalian SVZ. Here, we established a zebrafish model to study injury-induced neurogenesis in the adult brain. We show that the adult zebrafish brain possesses a remarkable capacity for neuronal regeneration. Telencephalon injury prompted the proliferation of neuronal precursor cells (NPCs) in the VZ of the injured hemisphere, compared with in the contralateral hemisphere. The distribution of NPCs, viewed by BrdU labeling and ngn1-promoter-driven GFP, suggested that they migrated laterally and reached the injury site via the subpallium and pallium. The number of NPCs reaching the injury site significantly decreased when the fish were treated with an inhibitor of γ-secretase, a component of the Notch signaling pathway, suggesting that injury-induced neurogenesis mechanisms are at least partly conserved between fish and mammals. The injury-induced NPCs differentiated into mature neurons in the regions surrounding the injury site within a week after the injury. Most of these cells expressed T-box brain protein (Tbr1), suggesting they had adopted the normal neuronal fate in this region. These results suggest that the telencephalic VZ contributes to neural tissue recovery following telencephalic injury in the adult zebrafish, and that the adult zebrafish is a useful model for regenerative medicine.
- SourceAvailable from: Angela Gritti[show abstract] [hide abstract]
ABSTRACT: The postnatal subventricular zone (SVZ) is a niche for continuous neurogenesis in the adult brain and likely plays a fundamental role in self-repair responses in neurodegenerative conditions. Maintenance of the pool of neural stem cells within this area depends on cell-cell communication such as that provided by the Notch signaling pathway. Notch1 receptor mRNA has been found distributed in different areas of the postnatal brain including the SVZ. Although the identity of Notch1-expressing cells has been established in the majority of these areas, it is still unclear what cell types within the SVZ are expressing components of this pathway. Here we demonstrate that most of expression of Notch1 in the adult SVZ occurs in polysialylated neural cell adhesion molecule (PSA-NCAM)-positive neural precursors and in glial fibrillary acidic protein-positive SVZ astrocytes. Notch1 was also found in PSA-NCAM-positive neuroblasts located within the rostral migratory stream (RMS) but much less in those that have reached the olfactory bulb. We show that two of the naturally occurring Notch1 activators, Jagged1 and Delta1, are also expressed in the SVZ and within the RMS in the adult mouse brain. Finally, using a model of cortical stab wound, we show that the astrogliogenic response of the SVZ to injury is accompanied by activation of the Notch pathway.Developmental Neuroscience 02/2006; 28(1-2):81-91. · 3.41 Impact Factor
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ABSTRACT: The subventricular zone (SVZ) generates the largest number of migratory cells in the adult brain. SVZ neuroblasts migrate to the olfactory bulbs (OB) in the adult, whereas during development, SVZ cells migrate into many adjacent nuclei. Previously, we showed that cerebral cortex injury in the adult causes molecular and cellular changes which may recapitulate the developmental migratory directions. Consistent with this, growth factors, as well as models of illness or injury can cause adult SVZ cells to migrate into non-olfactory bulb nuclei. Here, we tested the hypothesis that cerebral cortex injury in the adult mouse induces changes in migration, by labeling adult SVZ cells with a retroviral vector and examining the distribution of cells 4 days and 3 weeks later. Four days after cortical lesions, disproportionately fewer retrovirally-labeled cells had migrated to the olfactory bulb in lesioned mice than in controls. Conversely, the number of cells found in non-olfactory bulb regions (primarily the area of the lesion and the corpus callosum) was increased in lesioned mice. The morphology of these emigrated cells suggested that they were differentiating into glial cells. Three weeks after cortical injury, the majority of retrovirally-labeled cells in both groups of mice had migrated into the granule and periglomerular layers of the olfactory bulb. At 3 weeks, we still observed retrovirally-labeled glial cells in the corpus callosum and in the area of the injury in lesioned mice. These results suggest that cortical lesions cause a transient change in migration patterns of SVZ progeny, which is characterized by decreases in migration to the olfactory bulb but increased migration towards the injury. Our studies also suggest that cortical lesions induce the production of new glial cells which survive for at least 3 weeks after injury. The data support the concept that in the adult, SVZ cells can generate progeny that migrate towards injured areas and thus potentially be harnessed for neural repair.Brain Research 02/2004; 996(2):213-26. · 2.88 Impact Factor
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ABSTRACT: In contrast to mammals, adult teleost fish exhibit an enormous potential to regenerate neuronal tissue after injuries to the CNS. By combining a well-defined cerebellar lesion paradigm with differential proteome analysis at a post-lesion survival time of 3 days, we screened for protein candidates involved in repair of the fish brain. Out of nearly 900 protein spots detected on 2-D gels, spot intensity was significantly increased at least twofold in 30 spots and decreased to at least half the intensity of control tissue in 23 spots. The proteins associated with 24 of the spots were identified by PMF and MS/MS fragmentation. The cellular localization and the spatiotemporal patterns of two of these proteins, beta-actin and beta-tubulin, were further characterized through immunohistochemistry. Comparison of the observed changes in protein abundance with the previously characterized events underlying regeneration of the cerebellum suggests that the proteins identified are especially involved in cellular proliferation and survival, as well as axonal sprouting.PROTEOMICS 02/2006; 6(2):677-96. · 4.13 Impact Factor