Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia.
Mol Psychiatry. 2014 Apr;19(4):486-94. doi: 10.1038/mp.2013.45. Epub 2013 Apr 30.
Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders.
精神分裂症（SZ）是一种以神经元功能障碍为特征的复杂疾病。尽管有缺陷的选择性剪接与 SZ 有关，但负责的分子机制尚不清楚。此外，人们对神经元激活的早期转录组反应的了解有限。在这里，我们对这些转录组反应进行了分析，结果表明，长非编码 RNA（lncRNA）受神经元激活的动态调节，包括先前涉及脑和视网膜发育的 lncRNA Gomafu 的急性下调。此外，我们证明 Gomafu 直接与剪接因子 QKI 和 SRSF1（丝氨酸/精氨酸丰富的剪接因子 1）结合，Gomafu 的失调导致类似于在 SZ 中观察到的典型 SZ 相关基因 DISC1 和 ERBB4 的选择性剪接模式。最后，我们表明，在 SZ 患者的颞上回皮质灰质中，Gomafu 的表达下调。这些结果在神经元功能中的活性调节 lncRNA 和选择性剪接之间建立了功能联系，并表明它们的失调可能导致神经紊乱。
