Abstract
Oligodendrocyte (OLG)-related abnormalities have been broadly observed in schizophrenia (SZ); however, the etiology of these abnormalities remains unknown. As SZ is broadly believed to be a developmental disorder, the etiology of the myelin abnormalities in SZ may be related to OLG fate specification during development. Noncoding RNAs (ncRNAs) are an important part of multifaceted transcriptional complexes participating in neurogenic commitment and regulation of postmitotic cell function. The long ncRNA, NEAT1, is a structural component of paraspeckles (subnuclear bodies in interchromatin regions) that may control activity of developmental enhancers of OLG fate specification. Gene expression studies of multiple cortical regions from individuals with SZ showed strong downregulation of NEAT1 levels relative to controls. NEAT1-deficient mice show significant decreases in the numbers of OLG-lineage cells in the frontal cortex. To gain further insight into biological processes affected by NEAT1 deficiency, we analyzed RNA-seq data from frontal cortex of NEAT1-/- mice. Analyses of differentially expressed gene signature from NEAT1-/- mice revealed a significant impact on processes related to OLG differentiation and RNA posttranscriptional modification with the underlying mechanisms involving Wnt signaling, cell contact interactions, and regulation of cholesterol/lipid metabolism. Additional studies revealed evidence of co-expression of SOX10, an OLG transcription factor, and NEAT1, and showed enrichment of OLG-specific transcripts in NEAT1 purified chromatin isolates from human frontal cortex. Reduced nuclear retention of quaking isoform 5 in NEAT1-/- mice shed light on possible mechanism(s) responsible for reduced expression of OLG/myelin proteins and supported the involvement of NEAT1 in oligodendrocyte function.