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.

在精神分裂症（SZ）中已广泛观察到与少突胶质细胞（OLG）相关的异常。然而，这些异常的病因仍是未知的。由于普遍认为SZ是一种发育障碍，因此SZ中髓磷脂异常的病因可能与OLG在发育过程中的命运有关。非编码RNA（ncRNA）是参与神经源性承诺和有丝分裂后细胞功能调控的多面转录复合体的重要组成部分。长的ncRNA NEAT1是斑点旁的结构成分（染色质间区域的亚核小体），可以控制OLG命运规范的发育增强子的活性。来自SZ个体多个皮质区域的基因表达研究表明NEAT1强烈下调相对于控件的级别。缺乏NEAT1的小鼠额叶皮层中的OLG谱系细胞数量显着减少。为了进一步了解受NEAT1缺乏症影响的生物学过程，我们分析了NEAT1 ^-/-小鼠额叶皮层的RNA-seq数据。对来自NEAT1 ^-/-小鼠的差异表达基因签名的分析显示，其与OLG分化和RNA转录后修饰有关的过程具有重大影响，其潜在机制涉及Wnt信号传导，细胞接触相互作用和胆固醇/脂质代谢的调节。进一步的研究揭示了SOX10共表达的证据，一个OLG转录因子和NEAT1，并且在人额皮质的NEAT1纯化染色质分离物中显示了OLG特异性转录物的富集。NEAT1 ^-/-小鼠体内地震同工型5的核保留降低，阐明了导致OLG /髓磷脂蛋白表达降低的可能机制，并支持NEAT1参与少突胶质细胞功能。