RNA-seq of oligodendroglia progenitor cells(OPCs) isolated from WT and DISC1-Δ3 mice

Disrupted-in-schizophrenia-1 (DISC1), as one of the schizophrenia susceptibility genes highly expressed in oligodendrocyte precursor cells (OPCs), impacts oligodendroglial differentiation and myelination. Several DISC1 splicing variants, including DISC1-Δ3 (a DISC1 transcript with deleted exon 3 in a single allele), are abnormally upregulated in human schizophrenia patients, however, how they trigger the onset of the disease has not been explored yet. Here, we generate a mouse line that mimics human DISC1-Δ3 in oligodendrocyte lineage cells, and demonstrate that hypertrophic OPCs rather than myelin, are responsible for the neuronal deficits and schizophrenia-like symptoms. RNAseq was performed to analyze the transcriptome change in DISC1-Δ3 OPC, revealing that DISC1-Δ3 elevates the Wnt pathway activity in OPCs, which promotes Wif1 expression, thereby leading to disrupted synapse formation in neighboring neurons. Interfering or knockout of Wif1 in DISC1-Δ3 OPCs could rescue neuronal synaptic and functional deficits in our mouse model. Our findings shed light on the myelination-independent role of OPCs on the onset of schizophrenia, and may pave the way for new rational lines of inquiry in developing therapeutic strategies for schizophrenia. RNA-seq was performed to understand the transcriptome change in DISC1-Δ3 forced expressed OPC in vivo Mice were divided in 2 groups: wt: control group. ko: NG2-CreERTM: DISC1 exon3 fl/+ (DISC1 ∆3) mice. Tamoxifen was given at the gavage for 4 consecutive days (p4-p7).On postnatal day 7, mice were sacrificed to isolate OPCs from the brain by pdgfrα immunopanning.