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The basic helix–loop–helix transcription factor Olig2 suppresses neurogenesis following brain injury in adulthood.

The adult brain's ability to generate new neurons in circumscribed regions indicates the potential for exploiting intrinsic mechanisms for neuronal repair following degeneration or injury. Despite this, there has been a failure to generate new neurons in other regions following brain injury. So, are there factors that suppress neurogenesis in these non-neurogenic regions following injury in adulthood? Magdalena Götz and colleagues set out to address this question, and showed that the basic helix–loop–helix transcription factor Olig2 (oligodendrocyte transcription factor 2) is a restricting factor.

GFP-positive cells after antagonization of endogenous OLIG2 in the lesioned brain stained positive for doublecortin (dcx; red), indicative of newly generated neurons (left). Expression of the neurogenic transcription factor PAX6 (red) in the same experimental setting (right). Image courtesy of A. Buffo, University of Turin, Italy, and National Research Center for Environment and Health, Munich, Germany.

Götz and colleagues investigated the effects of several neurogenic transcription factors — including Pax6, Ngn2, Mash1 and Gsh2 — on neurogenesis in mice following stab wounds or focal ischaemia, and in mice with amyloid plaque deposition. All of these transcription factors are involved in specifying neuronal fate during development, and are found in precursor cells in the subendymal zone. As expected, they were not present in injured cells, in line with the absence of neurogenesis. However, OLIG2, but not OLIG1, was abundant in a range of glial cell populations following injury, but not in intact regions.

This elevated number of OLIG2-positive cells was apparent in all three injury paradigms, although the mechanisms that prompted this increase differed according to injury type. Stab wounds led to a rise in proliferation of OLIG2-positive cells, whereas amyloid plaque deposition resulted in upregulation of OLIG2 at the transcriptional level.

Next, these researchers looked specifically at the action of OLIG2 following stab wounds by disrupting its function through injection of retroviral vectors containing a dominant-negative form of OLIG2 into the injured region. Crucially, preventing OLIG2 activity triggered the generation of cells that acquired the hallmarks of immature neurons. This suggests that glial cells have the potential to generate neurons following injury in adulthood.

Interestingly, PAX6 was seen in some cells in which OLIG2 function had been suppressed, which indicates that OLIG2 normally prevents the action of PAX6 after injury. Transduction of cells with a PAX6-containing retrovirus led to a further increase in neurogenesis from cells that typically do not generate neurons.

Only a relatively small number of these cells differentiated into mature neurons, so future studies need to focus on mechanisms to promote survival and differentiation. Nevertheless, this work offers vital clues towards a potential therapeutic avenue for the induction of neurogenesis in the adult brain following even severe injuries.

Alison Rowan

References

Buffo, A. et al. Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc. Natl Acad. Sci. USA 102, 18183–18188 (2005) | Article | PubMed |