Origin of Oligodendrocytes in the Subventricular Zone of the Adult Brain

Harvard University, Cambridge, Massachusetts, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 08/2006; 26(30):7907-18. DOI: 10.1523/JNEUROSCI.1299-06.2006
Source: PubMed


Glial fibrillary acidic protein (GFAP)-positive astrocytes (type B cells) in the subventricular zone (SVZ) generate large numbers of new neurons in the adult brain. SVZ stem cells can also generate oligodendrocytes in vitro, but it is not known whether these adult primary progenitors generate oligodendrocytes in vivo. Myelin repair and oligodendrocyte formation in the adult brain is instead associated with glial-restricted progenitors cells, known as oligodendrocyte progenitor cells (OPCs). Here we show that type B cells also generate a small number of nonmyelinating NG2-positive OPCs and mature myelinating oligodendrocytes. Some type B cells and a small subpopulation of actively dividing type C (transit-amplifying) cells expressed oligodendrocyte lineage transcription factor 2 (Olig2), suggesting that oligodendrocyte differentiation in the SVZ begins early in the lineage. Olig2-positive, polysialylated neural cell adhesion molecule-positive, PDGF receptor alpha-positive, and beta-tubulin-negative cells originating in the SVZ migrated into corpus callosum, striatum, and fimbria fornix to differentiate into the NG2-positive nonmyelinating and mature myelinating oligodendrocytes. Furthermore, primary clonal cultures of type B cells gave rise to oligodendrocytes alone or oligodendrocytes and neurons. Importantly, the number of oligodendrocytes derived from type B cells in vivo increased fourfold after a demyelinating lesion in corpus callosum, indicating that SVZ astrocytes participate in myelin repair in the adult brain. Our work identifies SVZ type B cells as progenitors of oligodendrocytes in normal and injured adult brain.

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    • "to migrate to the lesion area upon CNS disease (Goings et al, 2004; Sundholm-Peters et al, 2005; Menn et al, 2006; Benner et al, 2013) (Fig 3A). Our results revealed that BrdU+Thbs4+ SVZ-generated astrocytes as well as BrdU+Olig2+ C cells co-express GFAP in the lesion area at 10 days after SWI and therefore contribute to the cortical lesion astrocyte population and are the potential source for Id3-regulated NSPC differentiation into astrocytes after injury (Fig 3A and B). "
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    ABSTRACT: Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP-2 and Id3 up-regulation in the SVZ stem cell niche. Id3(-/-) adult NSPCs failed to differentiate into BMP-2-induced astrocytes, while NSPCs deficient for the Id3-controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP-2. Mechanistically, E47 repressed the expression of several astrocyte-specific genes in adult NSPCs. These results identify Id3 as the BMP-2-induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury.
    The EMBO Journal 10/2015; DOI:10.15252/embj.201591118 · 10.43 Impact Factor
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    • "Location in the V-SVZ might be associated not only with differences in SHH signaling levels, but also other signaling pathways. Similarly, high SHH signaling in V-SVZ progenitors is not always associated with high oligodendrogenesis; the ventral V-SVZ has high Gli1 expression, but produces few oligodendrocytes postnatally (Kessaris et al., 2006; Menn et al., 2006). These results reveal a dorsal domain in the juvenile telencephalon with high levels of SHH signaling, where many oligodendrocytes are produced. "
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    ABSTRACT: Neural stem cells in different locations of the postnatal mouse ventricular-subventricular zone (V-SVZ) generate different subtypes of olfactory bulb (OB) interneurons. High Sonic hedgehog (SHH) signaling in the ventral V-SVZ regulates the production of specific subtypes of neurons destined for the OB. Here we found a transient territory of high SHH signaling in the dorsal V-SVZ beneath the corpus callosum (CC). Using intersectional lineage tracing in neonates to label dorsal radial glial cells (RGCs) expressing the SHH target gene Gli1, we demonstrate that this region produces many CC cells in the oligodendroglial lineage and specific subtypes of neurons in the OB. The number of oligodendroglial cells generated correlated with the levels of SHH signaling. This work identifies a dorsal domain of SHH signaling, which is an important source of oligodendroglial cells for the postnatal mammalian forebrain.
    Stem Cell Reports 09/2015; 5(4). DOI:10.1016/j.stemcr.2015.08.013 · 5.37 Impact Factor
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    • "The OPCs are maintained as a slowly proliferating or quiescent state and can differentiate into mature oligodendrocytes and myelinate axons during adulthood, which suggest adult OPCs are concerned with myelin sheath replacement (Rivers et al. 2008). It is shown that type B cells in the subventricular zone (SVZ) are the origin of oligodendrocytes in normal and injured adult brains (Menn et al. 2006). Voluntary exercise increases oligodendrogenesis in the thoracic segment of the adult spinal cord (Krityakiarana et al. 2010). "
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    ABSTRACT: Evidence have been accumulated that continuous oligodendrogenesis occurs in the adult mammalian brain. The fornix, projection and commissure pathway of hippocampal neurons, carries signals from the hippocampus to other parts of the brain and has critical role in memory and learning. However, basic characterization of adult oligodendrogenesis in this brain region is not well understood. In the present study, therefore, we aimed to examine the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) and the effect of acute inflammatory stimulation on oligodendrogenesis in the fornix of adult mouse. We demonstrated the proliferation of OPCs and a new generation of mature oligodendrocytes by using bromodeoxyuridine and Ki67 immunohistochemistry. Oligodendrogenesis of adult fornix was also demonstrated by using oligodendrocyte transcription factor 2 transgenic mouse. A single systemic administration of lipopolysaccharide (LPS) attenuated proliferation of OPCs in the fornix together with reduced proliferation of hippocampal neural stem/progenitor cells. Time course analysis showed that a single administration of LPS attenuated the proliferation of OPCs during 24-48h. On the other hand, consecutive administration of LPS did not suppress proliferation of OPCs. The treatment of LPS did not affect differentiation of OPCs into mature oligodendrocytes. Treatment of a microglia inhibitor minocycline significantly attenuated basal proliferation of OPCs under normal condition. In conclusion, the present study indicates that continuous oligodendrogenesis occurs and a single administration of LPS transiently attenuates proliferation of OPCs without changing differentiation in the fornix of the adult mouse brains.
    Brain Research 09/2015; 1627:52-69.. DOI:10.1016/j.brainres.2015.09.011 · 2.84 Impact Factor
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