Credit: SUPERSTOCK

Oligodendrocyte transcription factor 2 (OLIG2) has multiple roles in mammalian CNS development, determining neuronal and glial fates, and instructing neural progenitors to undergo proliferation or differentiation. The mechanisms underlying these effects remain unclear; however, two new studies reveal that the phosphorylation status of OLIG2 is a key determinant of this transcription factor's actions.

In vertebrate embryos, a subgroup of neuroepithelial stem cells in the developing spinal cord produces motor neurons before switching to generate oligodendrocyte precursors. Li et al. showed that motor neuron production in mice was associated with OLIG2 phosphorylation at Ser147, whereas oligodendrocyte precursor production was characterized by dephosphorylation at this site. Interestingly, transgenic mouse embryos expressing a mutant form of OLIG2 in which Ser147 was replaced with an alanine residue — precluding phosphorylation at this site — failed to generate motor neurons but still produced oligodendrocyte precursors.

Wild-type OLIG2 preferentially forms homodimers or OLIG2–OLIG1 heterodimers. The authors found that, by contrast, Ala147 OLIG2 was more likely to dimerize with neurogenin 2. Thus, in embryonic spinal cord, the phosphorylation status of OLIG2 at Ser147 influences neural cell specification, possibly through an effect on the dimerization properties of this transcription factor.

During later CNS development, OLIG2 function shifts from promoting neural progenitor cell proliferation to directing oligodendrocyte differentiation. Sun et al. examined whether phosphorylation changes in OLIG2 were associated with divergent activities.

The authors identified three serine residues near the amino terminus of OLIG2 that could be phosphorylated. Phosphorylation levels of this triple serine motif correlated with the levels of neural progenitor cell proliferation in late-stage mouse embryos and declined rapidly with postnatal oligodendrocyte precursor differentiation. Moreover, mimicking constitutive phosphorylation at these sites promoted neural progenitor cell proliferation in secondary neurosphere assays. Thus, phosphorylaton of OLIG2 at the triple serine motif promotes neural progenitor cell proliferation and is developmentally regulated.

OLIG2 expression is required for tumour formation in a mouse model of malignant glioma. Mimicking constitutive phosphorylation of OLIG2 at the triple serine motif promoted tumorigenesis in this model. Furthermore, the phosphorylation state of OLIG2 in neurospheres derived from human gliomas was similar to that observed in mouse neural progenitors. A companion study by Mehta et al. revealed that phosphorylated OLIG2 might promote gliomal cell proliferation through the suppression of p53 function.

These studies indicate that phosphorylation has an integral role in determining OLIG2 function in CNS development. The study by Sun et al. suggests that the amino-terminal triple phosphoserine motif of OLIG2 constitutes a target for anti-glioma therapy development.