Gain-of-Function of Olig Transcription Factors Enhances Oligodendrogenesis and Myelination

The basic helix-loop-helix transcription factors Olig1 and Olig2 are required for oligodendrocyte specification and differentiation during central nervous system (CNS) development but the effects of overexpression of these factors in murine development are not well understood. To test whether Olig1 and Olig2 may reprogram CNS stem/progenitors toward an oligodendroglial fate for myelination, we generated transgenic mice with doxycycline (Dox)-inducible expression of Olig1 or Olig2 in nestin-expressing stem/progenitor cells of the CNS. Overexpression of Olig1 or Olig2 from E8.5 to E12.5 was sufficient to promote the generation of Platelet-Derived Growth Factor Receptor alpha 1 oligodendrocyte precursors (OPCs) in the spinal cord. We also demonstrated that overexpression of Olig2, but not Olig1, enhanced the stem/progenitor cell proliferation and generation of motoneuron precursors and inhibited the development of V3 interneurons. In the postnatal brain, Dox-inducible expression of Olig2 but not Olig1 in nestin+ stem/progenitors of the subventricular zone increased the generation of OPCs that migrated and differentiated into mature oligodendrocytes in the corpus callosum, cortex and olfactory bulb, leading to increased and precocious myelination. Altogether, our data indicate that Olig2 is a potential therapeutic target to enhance myelination and remyelination in the CNS. STEM CELLS 2010;28:1611-1622