Modulation of the Sonic Hedgehog Pathway Normalizes Expression of Olig2 in pre-OPCs in Down Syndrome

Down syndrome (DS), the most common genetic form of intellectual disability, is associated with a decrease in brain white matter. To study the mechanism of this deficit, we differentiated two isogenic lines of induced pluripotent stem cells (iPSCs) derived from people with DS into neural progenitor cells (NPCs) and pre-oligodendrocyte progenitor cells (pre-OPCs) and spatially patterned them to have either brain-like or spinal cord-like molecular characteristics. In the spinal cord-like trisomic cells we found no difference in expression of Olig2 or Nkx2.2, two transcription factors essential for commitment to the OL lineage. However, in the brain-like trisomic pre-OPCs, Olig2 is significantly upregulated and is associated with reduced transition to OPC fate. This gene dysregulation can be normalized by increasing the concentration of SAG during differentiation. These results underscore the importance of regional and cell type differences in gene expression in DS and show that reduced responsiveness of trisomic cells to Sonic hedgehog signaling may drive the first perturbed step of OL differentiation in DS.