Sox2-Mediated Conversion of NG2 Glia into Induced Neurons in the Injured Adult Cerebral Cortex

Summary

The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 glia into induced doublecortin (DCX) ⁺ neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroglial and astroglial cells into DCX ⁺ cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 glia represent a potential target for reprogramming strategies toward cortical repair.

Graphical Abstract

Highlights

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  Sox2 or Sox2/ Ascl1 can convert glia into induced DCX ⁺ neurons in the injured cortex

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  Sox10-iCreER ^T2-mediated fate mapping shows that induced neurons are NG2 glia derived

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  Induced neurons receive (or retain) synapses from preexisting neurons

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  Without prior injury, Sox2 does not convert cortical macroglia into neurons

Abstract

In this article, Götz, Berninger, and colleagues show that forced expression of the transcription factor Sox2, alone or in combination with Ascl1, can induce direct in vivo lineage reprogramming of NG2 glia into induced neurons in the adult mouse cerebral cortex following severe stab wound injury. These findings identify NG2 glia as targets for neuronal cell replacement.