Calarco John A, Superina Simone, O'Hanlon Dave, Gabut Mathieu, Raj Bushra, Pan Qun, Skalska Ursula, Clarke Laura, Gelinas Danielle, van der Kooy Derek, Zhen Mei, Ciruna Brian, Blencowe Benjamin J
Banting and Best Department of Medical Research, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada.
Cell. 2009 Sep 4;138(5):898-910. doi: 10.1016/j.cell.2009.06.012.
Alternative splicing is a key process underlying the evolution of increased proteomic and functional complexity and is especially prevalent in the mammalian nervous system. However, the factors and mechanisms governing nervous system-specific alternative splicing are not well understood. Through a genome-wide computational and expression profiling strategy, we have identified a tissue- and vertebrate-restricted Ser/Arg (SR) repeat splicing factor, the neural-specific SR-related protein of 100 kDa (nSR100). We show that nSR100 regulates an extensive network of brain-specific alternative exons enriched in genes that function in neural cell differentiation. nSR100 acts by increasing the levels of the neural/brain-enriched polypyrimidine tract binding protein and by interacting with its target transcripts. Disruption of nSR100 prevents neural cell differentiation in cell culture and in the developing zebrafish. Our results thus reveal a critical neural-specific alternative splicing regulator, the evolution of which has contributed to increased complexity in the vertebrate nervous system.
可变剪接是蛋白质组和功能复杂性增加进化背后的关键过程，在哺乳动物神经系统中尤为普遍。然而，调控神经系统特异性可变剪接的因素和机制尚未完全了解。通过全基因组计算和表达谱分析策略，我们鉴定出一种组织和脊椎动物限制性丝氨酸/精氨酸（SR）重复剪接因子，即100 kDa神经特异性SR相关蛋白（nSR100）。我们发现nSR100调控一个广泛的脑特异性可变外显子网络，这些外显子在神经细胞分化相关基因中富集。nSR100通过增加神经/脑富集的多嘧啶序列结合蛋白水平并与其靶转录本相互作用来发挥作用。nSR100的破坏会阻止细胞培养和发育中的斑马鱼的神经细胞分化。因此，我们的结果揭示了一种关键的神经特异性可变剪接调节因子，其进化促成了脊椎动物神经系统复杂性的增加。
