These anatomic observations were especially intriguing in light of the differential gene expression pattern of the SCZ hGPCs, which revealed that the cells were deficient not only in early glial differentiation–associated transcripts, but also in genes that encode for synaptic proteins typically associated with transducing activity-dependent signals (Sudhof, 2008). Together, these anatomic and transcriptional data suggest that SCZ hiPSC-derived GPCs might be subject to impaired phenotypic differentiation, that might result in their neglect of the local neuronal signals that typically regulate the expansion and maturation of GPCs(Barres and Raff, 1993); this might account for their rapid transit through the white matter into the overlying cortex, and hence the diminished callosal GPC density and hypomyelination of SCZ chimeric shiverer mice (Figure 2). Thus, the myelination defect in SCZ hGPC chimeras appeared due to both deficient oligodendrocytic differentiation and the relative dearth of SCZ hGPCs remaining within the white matter. Moreover, astrocytic differentiation from SCZ hGPCs was also impaired, and may have contributed further to hypomyelination in the SCZ glial chimeras, given the metabolic dependence of mature oligodendrocytes upon local astrocytes (Amaral et al., 2013; John, 2012).
