Regional- and temporal-dependent changes in the differentiation of Olig2 progenitors in the forebrain, and the impact on astrocyte development in the dorsal pallium

Abstract

Olig2 is a basic helix-loop-helix transcription factor essential for oligodendrocyte and motoneuron development in the spinal cord. Olig2-positive (Olig2+) cells in the ventricular zone of the ventral telencephalon have been shown to differentiate into GABAergic and cholinergic neurons. However, the fate of Olig2 lineage cells in the postnatal forebrain has not been fully described and Olig2 may regulate the development of both astrocytes and oligodendrocytes. Here, we examined the fate of embryonic Olig2+ progenitors using a tamoxifen-inducible Cre/loxP system. Using long-term lineage tracing, Olig2+ cells in the early fetal stage primarily differentiated into GABAergic neurons in the adult telencephalon, while those in later stages gave rise to macroglial cells, both astrocytes and oligodendrocytes. Olig2+ progenitors in the diencephalon developed into oligodendrocytes, as observed in the spinal cord, and a fraction developed into glutamatergic neurons. Olig2 lineage oligodendrocytes tended to form clusters, probably due to local proliferation at the site of terminal differentiation. In spite of the abundance of Olig2 lineage GABAergic neurons in the normal neocortex, GABAergic neurons seemed to develop at normal density in the Olig2 deficient mouse. Thus, Olig2 is dispensable for GABAergic neuron specification. In contrast, at the late fetal stage in the Olig2 deficient mouse, astrocyte development was retarded in the dorsal neocortex, but not in the basal forebrain. Olig2 functions, therefore, in gliogenesis in the dorsal pallium. Short-term lineage tracing experiments revealed that the majority of late Olig2+ cells were not direct descendants of early Olig2+ progenitors in the fetal forebrain. These observations indicate that embryonic Olig2+ progenitor cells change their differentiative properties during development, and also that Olig2 plays a role in astrocyte development in a region-specific manner.

Progeny of Olig2-Expressing Progenitors in the Gray and White Matter of the Adult Mouse Cerebral Cortex

“…This is in pronounced contrast to the multitude of lineages observed to arise from this progenitor pool during development using even the very same mouse line Masahira et al, 2006;Miyoshi et al, 2007;Ono et al, 2008) or the NG2::CreERTM T2 line (Zhu et al, 2008). Importantly, during development, the different cell types arise from distinct sets of Olig2 ϩ progenitors (e.g., Olig2 ϩ cells that generate motoneurons do not share their lineage with those that generate oligodendrocytes) (Mukouyama et al, 2006;Wu et al, 2006).…”

“…The transcription factor Olig2 is a necessary regulator of oligodendrocyte and motoneurons development, and Olig2-expressing cells also generate cholinergic neurons, ependymal cells, as well as some astrocytes during development (Takebayashi et al, 2002;Ligon et al, 2006a;Masahira et al, 2006;Cai et al, 2007;Ono et al, 2008). Interestingly, Olig2 is also required for the specification of NG2 ϩ cells (Ligon et al, 2006b).…”

“…Interestingly, Olig2 is also required for the specification of NG2 ϩ cells (Ligon et al, 2006b). Similar to Olig2, NG2 is also expressed in progenitors of various lineages, including oligodendrocytes and astrocytes during development (Cai et al, 2007;Zhu et al, 2008;Ono et al, 2008), as well as multipotent progenitors in the postnatal brain (Belachew et al, 2003;Aguirre et al, 2004) and possibly even neuronal progenitors in the adult cerebral cortex (Dawson et al, 2000;Dayer et al, 2005;Tamura et al, 2007).…”

Emx2 and Foxg1 Inhibit Gliogenesis and Promote Neuronogenesis

“…In fact, two Drosophila Foxg1 orthologs, Sloppy paired-1 and -2 (Slp1 and Slp2), promote neuronogenesis at expenses of gliogenesis [59] and Foxg1 rescues the Slp1&2 null phenotype [60]. Such aberrant behavior of Foxg1-GOF NSCs might originate from unbalanced expression of Hes1, a key promoter of NSC self-renewal [61] and key gliogenesis promoters Coup-tf1, Nf1a, and Olig2 [62][63][64] (Supporting Information Fig. S11).…”

Combinatorial Gene Effects on the Neural Progenitor Pool in Down Syndrome

“…In this setting endogenous overexpression of a glial-associated gene S100B might drive gliogenic progenitors, while the inflammatory changes from oxidative stressors would further promote a gliocentric progenitor pool. Other candidate genes such as HSA21-localized Olig1 and Olig2 are basic helix-loop-helix (bHLH) transcription factors essential for development of oligodendrocytes (Jakovcevski and Zecevic, 2005;Lu et al, 2002;Takebayashi et al, 2002;Zhou and Anderson, 2002) or astrocytes (Cai et al, 2007;Marshall et al, 2005;Ono et al, 2008); and SYNJ1 could increase astrogliosis (Herrera et al, 2009). The number of Olig1/Olig2(+) progenitors increases in the injured CNS (Arnett et al, 2004), and Olig2(+) cells preferentially differentiate into GFAP-expressing astrocytes, the main contributors to glial scars which further secrete S100B Tatsumi et al, 2008).…”