Makeyev Eugene V, Zhang Jiangwen, Carrasco Monica A, Maniatis Tom
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Mol Cell. 2007 Aug 3;27(3):435-48. doi: 10.1016/j.molcel.2007.07.015.
Both microRNAs and alternative pre-mRNA splicing have been implicated in the development of the nervous system (NS), but functional interactions between these two pathways are poorly understood. We demonstrate that the neuron-specific microRNA miR-124 directly targets PTBP1 (PTB/hnRNP I) mRNA, which encodes a global repressor of alternative pre-mRNA splicing in nonneuronal cells. Among the targets of PTBP1 is a critical cassette exon in the pre-mRNA of PTBP2 (nPTB/brPTB/PTBLP), an NS-enriched PTBP1 homolog. When this exon is skipped, PTBP2 mRNA is subject to nonsense-mediated decay (NMD). During neuronal differentiation, miR-124 reduces PTBP1 levels, leading to the accumulation of correctly spliced PTBP2 mRNA and a dramatic increase in PTBP2 protein. These events culminate in the transition from non-NS to NS-specific alternative splicing patterns. We also present evidence that miR-124 plays a key role in the differentiation of progenitor cells to mature neurons. Thus, miR-124 promotes NS development, at least in part by regulating an intricate network of NS-specific alternative splicing.
微小RNA（microRNA）和前体mRNA可变剪接均与神经系统（NS）的发育有关，但这两条途径之间的功能相互作用却鲜为人知。我们证明，神经元特异性微小RNA miR-124直接靶向PTBP1（PTB/hnRNP I）mRNA，PTBP1编码非神经元细胞中前体mRNA可变剪接的全局抑制因子。PTBP1的靶标之一是PTBP2（nPTB/brPTB/PTBLP）前体mRNA中的一个关键盒式外显子，PTBP2是一种在NS中富集的PTBP1同源物。当这个外显子被跳过，PTBP2 mRNA会经历无义介导的衰变（NMD）。在神经元分化过程中，miR-124降低PTBP1水平，导致正确剪接的PTBP2 mRNA积累，PTBP2蛋白显著增加。这些事件最终导致从非NS特异性剪接模式向NS特异性剪接模式的转变。我们还提供证据表明，miR-124在祖细胞向成熟神经元的分化中起关键作用。因此，miR-124至少部分地通过调节NS特异性可变剪接的复杂网络来促进NS的发育。
