We observed that patient-derived neurospheres are smaller in size and that differentiated neurons display abnormal morphology, phenotypes shared with those seen in model mice for the 22q11.2 microdeletion (Df(16)A+/– mice and Df1 mice).4, 9, 42, 43 As a potentially relevant gene, we focused on DGCR8 among genes that are mapped on the deleted interval, because neurospheres generated from the hippocampus of Dgcr8+/− mice also showed size reduction.10 In addition, the Dgcr8+/− mice displayed working memory deficits and sensory information-processing deficits,9, 42 which are seen in schizophrenia patients. DGCR8 is essential for miRNA biogenesis.32 As the downstream targets of DGCR8, which may be causally linked to the observed phenotypes, we examined the miR-17/92 cluster and miR-106a/b.37 The patient-derived neurospheres showed reduced expression levels of miR-17/92 cluster members and miR-106a/b. Downregulation of the DGCR8 gene suppresses the conversion of a subset of pri-forms of miRNA to pre-miRNAs and results in the dampened generation of a particular subset of mature miRNAs.44 In the patient-derived neurospheres, the expression level of the pri-form of miR-106b was significantly increased, conforming to haploinsufficiency of DGCR8.
