Direct reprogramming of oligodendrocyte precursor cells into GABAergic inhibitory neurons by a single homeodomain transcription factor Dlx2.

Affiliation

Boshans LL(1), Soh H(1), Wood WM(1), Nolan TM(1), Mandoiu II(2)(3), Yanagawa Y(4), Tzingounis AV(1), Nishiyama A(5)(6)(7).
Author information:
(1)Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA.
(2)Department of Computer Science and Engineering, University of Connecticut, Storrs, CT, USA.
(3)Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA.
(4)Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, Japan.
(5)Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT, USA. [Email]
(6)Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA. [Email]
(7)The Connecticut Institute for Brain and Cognitive Sciences, University of Connecticut, Storrs, CT, USA. [Email]

Abstract

Oligodendrocyte precursor cells (NG2 glia) are uniformly distributed proliferative cells in the mammalian central nervous system and generate myelinating oligodendrocytes throughout life. A subpopulation of OPCs in the neocortex arises from progenitor cells in the embryonic ganglionic eminences that also produce inhibitory neurons. The neuronal fate of some progenitor cells is sealed before birth as they become committed to the oligodendrocyte lineage, marked by sustained expression of the oligodendrocyte transcription factor Olig2, which represses the interneuron transcription factor Dlx2. Here we show that misexpression of Dlx2 alone in postnatal mouse OPCs caused them to switch their fate to GABAergic neurons within 2 days by downregulating Olig2 and upregulating a network of inhibitory neuron transcripts. After two weeks, some OPC-derived neurons generated trains of action potentials and formed clusters of GABAergic synaptic proteins. Our study revealed that the developmental molecular logic can be applied to promote neuronal reprogramming from OPCs.