It has been reported that (i) miR-17/106 targets the MAPK14 transcript (encoding the α-isoform of p38 protein kinase) in mice and (ii) the miR-17/106-p38 axis is a critical regulator of the neurogenic-to-gliogenic transition competence.37 Therefore, the protein expression levels of p38α in patient-derived neurospheres were predicted to be increased by the downregulation of miR-17/92 cluster members. Conformingly, western blot analysis showed that the expression levels of p38α were significantly increased in patient-derived neurospheres (1.36-fold higher; P=0.0162) than those in controls (Figures 4a and b). On the basis of previously published studies,37, 38 we hypothesized that the upregulation of p38α is causally linked to the abnormal neuronal differentiation pattern (preferential gliogenic competence) in patient-derived neurospheres. If this is true, the abnormal differentiation phenotype could be at least partially rescued by inhibiting p38 activity. Consistent with this idea, treatments with a p38-specific inhibitor, SB203580,39, 40 produced a significantly higher number of neurons (P=0.0426) (Figures 4c and d) and a significant reduction of the astrocyte population (P=0.0394; Figures 4c and e) in samples derived from patients. The SB203580 treatment did not alter the fractions of neurons and astrocytes in control samples (Figures 4c–e).
