Oligodendrogliogenic and neurogenic adult subependymal zone neural stem cells constitute distinct lineages and exhibit differential responsiveness to Wnt signalling.

The adult mouse subependymal zone (SEZ) harbours adult neural stem cells (aNSCs) that give rise to neuronal and oligodendroglial progeny. However it is not known whether the same aNSC can give rise to neuronal and oligodendroglial progeny or whether these distinct progenies constitute entirely separate lineages. Continuous live imaging and single-cell tracking of aNSCs and their progeny isolated from the mouse SEZ revealed that aNSCs exclusively generate oligodendroglia or neurons, but never both within a single lineage. Moreover, activation of canonical Wnt signalling selectively stimulated proliferation within the oligodendrogliogenic lineage, resulting in a massive increase in oligodendrogliogenesis without changing lineage choice or proliferation within neurogenic clones. In vivo activation or inhibition of canonical Wnt signalling respectively increased or decreased the number of Olig2 and PDGFR- α positive cells, suggesting that this pathway contributes to the fine tuning of oligodendrogliogenesis in the adult SEZ.

Sox10-iCreERT2 : a mouse line to inducibly trace the neural crest and oligodendrocyte lineage.

SOX10 is a well-conserved and widely expressed transcription factor involved in the regulation of embryonic development and in the determination of cell fate. As it is expressed in neural crest cells, their derivatives and the oligodendrocyte lineage, mutations of the protein contribute to a variety of diseases like neurocristopathies, peripheral demyelinating neuropathies, and melanoma. Here, we report the generation of an inducible Sox10-iCreER(T2) BAC transgenic mouse line that labels, depending on the timepoint of induction, distinct derivatives of the otic placode and the neural crest as well as cells of the oligodendrocyte lineage. Surprisingly, we could show a neural crest origin of pericytes in the brain. Besides its use for fate-mapping, the Sox10-iCreER(T2) mouse line is a powerful tool to conditionally inactivate genes in the neural crest cells, their progeny and/or the oligodendrocyte lineage in a time-dependent fashion to gain further insights into their function and contribution to diseases.

Progenitors in the adult cerebral cortex: cell cycle properties and regulation by physiological stimuli and injury.

The adult brain parenchyma contains a widespread population of progenitors generating different cells of the oligodendrocyte lineage such as NG2+ cells and some mature oligodendrocytes. However, it is still largely unknown how proliferation and lineage decisions of these progenitors are regulated. Here, we first characterized the cell cycle length, proliferative fraction, and progeny of dividing cells in the adult cerebral cortex and then compared these proliferation characteristics after two distinct stimuli, invasive acute brain injury and increased physiological activity by voluntary physical exercise. Our data show that adult parenchymal progenitors have a very long cell cycle due to an extended G1 phase, many of them can divide at least twice and only a limited proportion of the progeny differentiates into mature oligodendrocytes. After stab wound injury, however, many of these progenitors re-enter the cell cycle very fast, suggesting that the normally long G1 phase is subject to regulation and can be abruptly shortened. In striking contrast, voluntary physical exercise shows the opposite effect with increased exit of the cell cycle followed by an enhanced and fast differentiation into mature oligodendrocytes. Taken together, our data demonstrate that the endogenous population of adult brain parenchymal progenitors is subject to profound modulation by environmental stimuli in both directions, either faster proliferation or faster differentiation.

Progeny of Olig2-expressing progenitors in the gray and white matter of the adult mouse cerebral cortex.

Despite their abundance, still little is known about the rather frequent, constantly proliferating progenitors spread throughout the adult mouse brain parenchyma. The majority of these progenitors express the basic-helix-loop-helix transcription factor Olig2, and their number further increases after injury. Here, we examine the progeny of this progenitor population by genetic fate mapping using tamoxifen-inducible Cre-recombination in the Olig2 locus to turn on permanent reporter gene expression in the adult brain. Consistent with Olig2 expression in proliferating NG2(+) progenitors, most reporter(+) cells seen shortly after initiating recombination at adult stages incorporated BrdU and contained the proteoglycan NG2 in both the gray (GM) and the white matter (WM) of the cerebral cortex. However, at longer time points after induction, we observed profound differences in the identity of reporter(+) cells in the WM and GM. Whereas most of the Olig2(+) progenitors had generated mature, myelinating oligodendrocytes in the WM, hardly any reporter(+) cells showing mature oligodendrocyte characteristics were detectable even up to 6 months after recombination in the GM. In the GM, most reporter(+) cells remained NG2(+), even after injury, but stopped proliferating rather soon after recombination. Thus, our results demonstrate the continuous generation of mature, myelinating oligodendrocytes in the WM, whereas cells in the GM generated mostly postmitotic NG2(+) glia.