Sonic hedgehog contributes to oligodendrocyte specification in the mammalian forebrain

This study addresses the role of Sonic hedgehog (Shh) in promoting the gene ration of oligodendrocytes in the mouse telencephalon, We show that in the forebrain, expression of the early oligodendrocyte markers Olig2, plp/dm20 and PDGFR alpha corresponds to regions of Shh expression. To directly test if Shh can induce the development of oligodendrocytes within the telencepha lon, we use retroviral vectors to ectopically express Shh within the mouse embryonic telencephalon. We find that infections with Shh-expressing retrov irus at embryonic day 9.5, result in ectopic Olig2 and PDGFR alpha expressi on by mid-embryogenesis, By postnatal day 21, cells expressing ectopic Shh overwhelmingly adopt an oligodendrocyte identity. To determine if the loss of telencephalic Shh correspondingly results in the loss of oligodendrocyte production, we studied Nkx2.1 mutant mice in which telencephalic expressio n of Shh is selectively lost. In accordance with Shh playing a role in olig odendrogenesis, within the medial ganglionic eminence of Nkx2.1 mutants, th e early expression of PDGFR alpha is absent and the level of Olig2 expressi on is diminished in this region. In addition, in these same mutants, expres sion of both Shh and plp/dm20 is lost in the hypothalamus. Notably, in the prospective amygdala region where Shh expression persists in the Nkx2.1 mut ant, the presence of plp/dm20 is unperturbed. Further supporting the idea t hat Shh is required for the in vivo establishment of early oligodendrocyte populations, expression of PDGFR alpha can be partially rescued by virally mediated expression of Shh in the Nkx2.1 mutant telencephalon. Interestingl y, despite the apparent requirement for Shh for oligodendrocyte specificati on in vivo, all regions of either wild-type or Nkx2.1 mutant telencephalon are competent to produce oligodendrocytes in vitro. Furthermore, analysis o f CNS tissue from Shh null animals definitively shows that, in vitro, Shh i s not required for the generation of oligodendrocytes. We propose that olig odendrocyte specification is negatively regulated in vivo and that Shh gene rates oligodendrocytes by overcoming this inhibition. Furthermore, it appea rs that a Shh-independent pathway for generating oligodendrocytes exists.