Stage-specific Regulation Of Oligodendrocyte Development In The Spinal Cord By Hedgehog Signaling

Oligodendrocytes are generated by the differentiation and maturation of OPCs.The failure of OPC differentiation is the major cause for ineffective myelin repair in demyelinating diseases;thus,identifying the molecular mechanisms that affect OPC differentiation is critical for understanding the myelination process and repairing after demyelinaion.Despite the extensive work outlining the importance of hedgehog(Hh)signaling in the commitment and generation of oligodendrocyte progenitor cells(OPCs),there are conflicting reports on the role of Hh signaling in regulating OL differentiation.In the present study,we systematically investigated OPC specification and differentiation in genetically modified mouse models of Smoothened(Smo),an essential component of the Hh signaling pathway in vertebrates.There are several novel findings in our study:(1)Disruption of Smo-mediated Hh signaling in neural progenitors significantly delayed OL differentiation in vivo;(2)Activation of Smo in NPCs is able to trigger transient ectopic OPC generation and precocious OL differentiation;(3)After the commitment of OL-lineage,sustained expression of Smo in OPCs promotes OPC proliferation but negatively regulates OL differentiation;(4)The induction of precocious OL differentiation in NPCs by Smo was due to co-expression of OLIG2 and NKX2.2.Based on our findings,we uncovered the stage-specific regulation of OL development by Smo-mediated Hh signaling,providing novel insights into the molecular regulation of OL differentiation and myelin development.