Direct reprogramming of non-neuronal cells to generate new neurons is a promising approach to repair damaged brains. Impact of the in vivo environment on neuronal reprogramming, however, is poorly understood. Here we show that regional differences and injury conditions have significant influence on the efficacy of reprogramming and subsequent survival of the newly generated neurons in the adult rodent brain. A combination of local exposure to growth factors and retrovirus-mediated overexpression of the neurogenic transcription factor Neurogenin2 can induce new neurons from non-neuronal cells in the adult neocortex and striatum where neuronal turnover is otherwise very limited. These two regions respond to growth factors and Neurogenin2 differently and instruct new neurons to exhibit distinct molecular phenotypes. Moreover, ischaemic insult differentially affects differentiation of new neurons in these regions. These results demonstrate strong environmental impact on direct neuronal reprogramming in vivo.
Bibliographical noteFunding Information:
We are grateful to T. Kitamura, Y. Ihara, G. Oliver, I. Dobashi, M. Nagao and M. Sugimori for reagents. We thank G. Keller and staff at the Veterinary Services Department, Matthew Kofron, Eric Brunskill, H -C.Liang and S. Smith for technical support. This study was supported by NIH/NINDS 1R01NS069893 to M.N. and K.C., Ohio Eminent Scholar Fund from the State of Ohio to M.N., AANS/CNS Research Award, Research Update in Neurosurgery and Neuroscience (RUNN) Resident Research Award and Mayfield Education and Research Foundation Grant to A.D.