Olig2 Directs Astrocyte and Oligodendrocyte Formation in Postnatal Subventricular Zone Cells

Abstract

The subventricular zone (SVZ) in the neonatal mammalian forebrain simultaneously generates olfactory interneurons, astrocytes, and oligodendrocytes. The molecular cues that enable SVZ progenitors to generate three distinct cell lineages without a temporal switching mechanism are not known. Here, we demonstrate that the basic helix-loop-helix transcription factor Olig2 plays a central role in this process. Olig2 is specifically expressed in gliogenic progenitors in the postnatal SVZ and by all glial lineages derived from this structure. By expressing normal and dominant-interfering forms of Olig2 in vivo, we show that Olig2 repressor function is both sufficient and necessary to prevent neuronal differentiation and to direct SVZ progenitors toward astrocytic and oligodendrocytic fates. Although Olig2 activity has been associated previously with motor neuron and oligodendrocyte development, our findings establish a previously unappreciated role for Olig2 in the development of astrocytes. Furthermore, these results indicate that Olig2 serves a critical role in pan-glial versus neuronal fate decisions in SVZ progenitors, making it the first intrinsic fate determinant shown to operate in the early postnatal SVZ.

Reduced EGFR signaling in progenitor cells of the adult subventricular zone attenuates oligodendrogenesis after demyelination

“…Our studies demonstrate that, at any postnatal age, at least 50% of the NG2 + cells in the SVZ are proliferative and that Cdk2 is a major molecular regulator of their proliferation throughout postnatal development (Belachew et al, 2002;Jablonska et al, 2007). The results of our previous studies also defined the following cellular and molecular properties of NG2 + cells in the SVZ Jablonska et al, 2007): i) NG2 + cells are found scattered through the wall of the lateral ventricle, but they are more abundant in the anterior SVZ; ii) NG2 + cells in the SVZ constitute approximately 12% and 3% of the total cell population at P8 and P30-60, respectively; iii) NG2 + cells in the SVZ are highly proliferative, as demonstrated by the percentages of NG2 + Ki67 + cells in the SVZ -56 and 32% at P8 and P30, respectively; iv) NG2 + cells of the SVZ express cellular markers of neural progenitor cells and stem cells, including the Lewis X antigen (LeX) (Capela and Temple, 2003), and the transcription factors Mash1, Olig2, and Dlx (Doetsch et al, 2002;Parras et al, 2004;Marshall et al, 2005;Menn et al, 2006;Kohwi et al, 2007;Parras et al, 2007); and v) NG2 + cells of the SVZ display a type-C cell phenotype, including expression of the EGFR, PSA-NCAM, and nestin (Capela and Temple, 2002;Doetsch et al, 2002). Consistent with our findings, other reports have also described the presence of NG2 + cells in the SVZ, and demonstrated diverse cellular and molecular properties of these progenitors in this neurogenic region, including co-expression of DCX Tamura et al, 2007), responsiveness to sonic hedgehog (Loulier et al, 2006), and Islet-1-induced migration into striatum (Rogelius et al, 2006).…”

Transforming growth factor α promotes sequential conversion of mature astrocytes into neural progenitors and stem cells

“…Lack of Olig2 expression in control cultures further supports astrocyte maturity and initial lack of progenitors. Indeed, whereas mature astrocytes lack Olig2 expression, this transcription factor is present in radial glial cells, glial-restricted progenitors and immature astrocytes (Marshall et al, 2005), and its expression has been shown to repress astrocytes differentiation (Fukuda et al, 2004;Muroyama et al, 2005). Serum starvation of the cultures prior growth factors addition, and possibly the repeated washes with ice-cold phosphate saline buffer initially designed to remove the microglial and oligodendroglial cells, which reside at the top of the cellular layer, might account for the lack of neural progenitors and stem cells in our astrocyte cultures.…”

“…Olig2 inhibits the differentiation of neural progenitors into astrocytes (Fukuda et al, 2004;Muroyama et al, 2005) and its expression is downregulated in vitro and in vivo in mature astrocytes (Fukuda et al, 2004;Marshall et al, 2005). Accordingly, a hardly detectable Olig2-immunoreactive signal was observed in control astrocytes (Figure 2g), whereas TGFa-treated cells exhibited a strong nuclear Olig2-immunoreactive signal (Figure 2h).…”

Expression of the transcription factor Olig2 in proliferating cells in the adult zebrafish telencephalon

“…We regard it as unlikely that these cells are neurons, as none of the olig2-positive cells expressed the neuronal marker HuC/ D. Interestingly, also the Mbp-negative olig2-expressing cells seem to have processes that appear as a punctate staining on the sections. In the mouse postnatal brain, olig2 not only labels oligodendrocytes, but also astrocytes (Marshall et al, 2005). However, 98% of the olig2 cells in the zebrafish telencephalic parenchyma are positive for sox10, which is a marker for the oligodendrocyte lineage.…”

“…In addition, they were shown to act as multipotent stem cells in vitro (Kondo and Raff, 2000;Nunes et al, 2003) and in vivo (Rivers et al, 2008;Zawadzka et al, 2010), which makes them interesting candidates for therapeutic applications in neurodegenerative diseases. Recent data suggest that the SVZ, similar to its generation of neurons for the olfactory bulbs via transit amplifying progenitors, can also generate new OPCs (Marshall et al, 2005;Menn et al, 2006). Olig2 is upregulated in response to brain injury and represses the expression of neurogenic factors.…”