Dando Owen, McQueen Jamie, Burr Karen, Kind Peter C, Chandran Siddharthan, Hardingham Giles E, Qiu Jing
Edinburgh Medical School, UK Dementia Research Institute at the University of Edinburgh, Edinburgh, United Kingdom.
Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, United Kingdom.
Front Mol Neurosci. 2024 Aug 29;17:1392408. doi: 10.3389/fnmol.2024.1392408. eCollection 2024.
Rodent studies have shown that alternative splicing in neurons plays important roles in development and maturity, and is regulatable by signals such as electrical activity. However, rodent-human similarities are less well explored. We compared basal and activity-dependent exon splicing in cortical-patterned human ESC-derived neurons with that in cortical mouse ESC-derived neurons, primary mouse cortical neurons at two developmental stages, and mouse hippocampal neurons, focussing on conserved orthologous exons. Both basal exon inclusion levels and activity-dependent changes in splicing showed human-mouse correlation. Conserved activity regulated exons are enriched in RBFOX, SAM68, NOVA and PTBP targets, and centered on cytoskeletal organization, mRNA processing, and synaptic signaling genes. However, human-mouse correlations were weaker than inter-mouse comparisons of neurons from different brain regions, developmental stages and origin (ESC vs. primary), suggestive of some inter-species divergence. The set of genes where activity-dependent splicing was observed only in human neurons were dominated by those involved in lipid biosynthesis, signaling and trafficking. Study of human exon splicing in mouse Tc1 neurons carrying human chromosome-21 showed that neuronal basal exon inclusion was influenced by cis-acting sequences, although may not be sufficient to confer activity-responsiveness in an allospecific environment. Overall, these comparisons suggest that neuronal alternative splicing should be confirmed in a human-relevant system even when exon structure is evolutionarily conserved.
啮齿动物研究表明，神经元中的可变剪接在发育和成熟过程中发挥重要作用，并且可由电活动等信号调节。然而，啮齿动物与人类之间的相似性尚未得到充分探索。我们比较了人胚胎干细胞来源的皮质模式神经元与小鼠胚胎干细胞来源的皮质神经元、两个发育阶段的原代小鼠皮质神经元以及小鼠海马神经元中基础和活性依赖的外显子剪接情况，重点关注保守的直系同源外显子。基础外显子包含水平和活性依赖的剪接变化均显示出人与小鼠之间的相关性。保守的活性调节外显子在RBFOX、SAM68、NOVA和PTBP的靶标中富集，并且集中在细胞骨架组织、mRNA加工和突触信号传导基因上。然而，人与小鼠之间的相关性弱于来自不同脑区、发育阶段和来源（胚胎干细胞与原代细胞）的小鼠神经元之间的种内比较，这表明存在一些种间差异。仅在人神经元中观察到活性依赖剪接的基因集主要由参与脂质生物合成、信号传导和运输的基因主导。对携带人类21号染色体的小鼠Tc1神经元中的人类外显子剪接研究表明，神经元基础外显子包含受顺式作用序列影响，尽管在异源环境中可能不足以赋予活性反应性。总体而言，这些比较表明，即使外显子结构在进化上是保守的，神经元可变剪接也应在与人类相关的系统中得到证实。
